Systems, methods, compositions and devices for in vivo magnetic resonance imaging of lungs using perfluorinated gas mixtures

ABSTRACT

Systems and methods for generating MRI images of the lungs and/or airways of a subject using a medical grade gas mixture comprises between about 20-79% inert perfluorinated gas and oxygen gas. The images are generated using acquired  19 F magnetic resonance image (MRI) signal data associated with the perfluorinated gas and oxygen mixture.

RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 13/577,926, filed Sep. 14, 2012, which is a 35 USC371 national phase application of PCT/US2011/025011, filed Feb. 16,2011, which claims the benefit of and priority to U.S. ProvisionalApplication Ser. No. 61/305,025 filed Feb. 16, 2010 and U.S. ProvisionalApplication Ser. No. 61/435,599 filed Jan. 24, 2011, the contents ofwhich are hereby incorporated by reference as if recited in full herein.

FIELD OF THE INVENTION

The present invention relates to non-invasive in vivo ¹⁹F MagneticResonance Imaging (“MRI”) using perfluorinated gas mixtures.

BACKGROUND OF THE INVENTION

The Centers for Disease Control (CDC) has stated that COPD (chronicobstructive pulmonary disease) has escalated to the 3^(rd) leading causeof death in this country. See, A M, Miniño, Xu J Q, and Kochanek K D(2010), ‘Deaths: Preliminary Data for 2008.’, National Vital StatisticsReports, 59 (2), John Walsh (President, COPD Foundation) remarked that“It's unacceptable that COPD has gone from the fourth leading cause tothe third twelve years sooner than what was originally projected. Thiswake-up call intensifies our declaration of war on COPD and points tothe importance of improved awareness, prevention, detection andtreatment to decrease the burden of COPD”. {Foundation, COPD (2010),‘New CDC Report Puts COPD in #3 Spot in Mortality Rates’} In contrast toother top causes of death, COPD is the only disease in the top ten thathas consistently increased in frequency over the past 4 decades.Consequently COPD represents one of the largest uncontrolled diseaseepidemics in the U.S.; it currently includes 15-20 million diagnosedcases with perhaps a similar number undiagnosed. In the U.S., there areapproximately 90 million current or former smokers, (Association, 2008);thus, a huge population is at risk of developing COPD. COPD is definedby the Global Initiative for Chronic Obstructive Lung Disease (GOLD) asa disease state characterized by airflow limitation that is not fullyreversible. Heron et al., “Deaths: Final Data for 2006.” National VitalStatistics Reports 57(14): 1-135 (2009).

There is clear recognition that COPD includes both emphysema and smallairway disease; however, there is little appreciation of how to identifyCOPD early—before there is significant airflow obstruction and clinicalimpairment. In addition, evidence from the COPD Gene study suggests thatCOPD is likely several diseases but currently the only tool that seemsto provide any clinical differentiation of the genotypes is “gastrapping” patterns assessed by HRCT (High Resolution X-ray ComputedTomography).

Current approaches for the evaluation of pulmonary lung function useglobal measures of pulmonary function such as spirometry (e.g., forcedexpiratory volume in 1 second (“FEV1”)) and whole body plethysmography.While spirometry is low cost and widely available, it does not yield anyregional information about ventilation distribution or ventilationdynamics in the lung.

Currently available lung imaging methods include x-ray CT, which offersanatomic detail but limited functional information, and nucleartechniques such as scintigraphy, which provide regional information atlow resolution in two dimensions rather than three (or more). Also,these modalities deliver ionizing radiation, which limits their repeatuse in patients, especially in clinical trials.

More recently, hyperpolarized gas MRI using the stable isotopes ³He and¹²⁹Xe has offered hope for non-invasive, regional assessment of lungfunction. Unfortunately, this technology is relatively expensive and hasnot been widely disseminated.

SUMMARY OF EMBODIMENTS OF THE INVENTION

Embodiments of the invention provide systems, methods and relateddevices that allow for static and/or dynamic in vivo ¹⁹F MRI of thelungs using perfluorinated gas and oxygen gas mixtures.

The term “perfluorinated gas” (“PFx” gas) refers to inert medical gradegases derived from common organic perfluorocarbon or otherperfluorinated compounds with the hydrogen atoms replaced with fluorineatoms.

Embodiments of the invention provide ways to evaluate ventilationdynamics (e.g., function) of a patient's lungs.

Embodiments of the invention can provide images of the gas spaces in thelung and be used for quantitative analysis of MR image data for lungfunction and/or regional ventilation assessment of the lung. Forexample, the MRI data can be used to assess, identify and/or visualizeregional ventilation data (e.g., pattern) associated with function,ventilation defects and/or gas trapping (regional and temporal).

Embodiments of the invention can provide dynamic “free-breathing” cineimages of a breathing lung (corresponding to a respiratory cycle). Someembodiments can provide dynamic images or pseudo-static images usinggated image data collection over a plurality of respiratory cycles of asubject and reconstructed in a variety of manners to accommodate therespiratory cycle. Other embodiments employ short and/or longbreath-hold techniques. Other embodiments include prospective orretrospective signal averaging of multiple image sets to improve theimage quality (signal to noise and contrast to noise).

Embodiments of the invention can generate be used to obtain both ¹Himages and ¹⁹F images in a single imaging session of a subject.Optionally, air-breaths and the PFx/oxygen gas breaths can be cycledduring the imaging session to alternate the ¹H and ¹⁹F image datacollection and/or to provide gas trapping data. Other embodimentsinclude sequential breath-hold images or time gated images to identifywash-in and wash-out information. These embodiments can be used to gradethe severity of any ventilation defects.

Changes in signal intensity of some of the PFx mixtures are sensitive tolocal oxygen concentration. In such an embodiment an estimate of oxygengas exchange (perfusion) can be accomplished using T1 weighed images orcalculated T1 images. It is noteworthy that this latter embodiment canuse a PFx agent with longer T1 relaxation times, e.g., above about 10ms, such as perfluoropropane (with a T1 relaxation time about 20 ms).

Embodiments of the invention can be used to obtain data to identifyventilation and/or perfusion variations (deficits or increases) beforeand after a physiologically active substance is administered to a humanor animal body to evaluate the efficacy of the drug treatment.

Embodiments of the invention can be carried out post-administration ofthe PFx gas mixture as a post administration data collection analysismethod to analyze signal data. The methods can, post administrationand/or post signal collection, generate images, generate ventilationdefect index, generate visual model of lung impairment and the like. Thepost-collection analysis can be carried out at any point in time afterthe delivery of the gas mixture, such as, for example, after the patientis removed from the MRI suite or magnet or when the patient is breathingoxygen, but in the MRI suite/magnet.

Embodiments of the invention are directed to post-collection analysisventilation assessment methods. The methods include generating at leastone of the following using pre-acquired ¹⁹F magnetic resonance image(MRI) signal data of a patient associated with a perfluorinated gas andoxygen mixture: (i) a cine of free-breathing images of the lungs of thesubject illustrating a temporal and spatial distribution of theperfluorinated gas in the lung space and lungs of the subject to provideventilation image data over at least one respiratory cycle;

(ii) at least one ventilation defect index for each of the right andleft lungs;

(iii) a ventilation defect index map showing a spatial distribution(pixel wise) of the lungs;

(iv) a visual output to a display, the output including a time sequenceof airflow data of the subject with a plurality of MRI images positionedaligned with an acquisition time, in the time sequence;

(v) a ventilation pattern associated with a forced ejection volume;

(vi) at least one histogram associated with wash-in and/or wash-out ofthe gas mixture;

(vii) at least one regional ventilation defect model showing intensityvariation pixel to pixel;

(viii) gas trapping images using wash in and/or wash out ¹⁹F MRI signaldata;

(ix) a visual output of a graphic analysis fit to a lung model ofventilation wash-in and/or wash-out with a plurality of MRI imagesdepicting functional information;

(x) a pattern of signal intensity depicting gas exchange to capillaryblood flow based on relaxation parameters (T1 and/or T2) and an impactof local oxygen concentration on the relaxation parameters; and

(xi) at least one histogram associated with wash-in and/or wash-out ofthe delivered gas mixture.

Still other embodiments are directed to methods of obtaining image dataof the lungs and/or airways of a subject. The methods include: (a)positioning a subject in a magnetic field associated with a high-fieldmagnet of an MRI scanner; (b) delivering a medical grade gas mixture tothe lung space of the subject, the gas mixture comprising between about20-79% inert perfluorinated gas and at least about 21% oxygen gas; (c)acquiring ¹⁹F magnetic resonance image (MRI) signal data associated withthe delivered perfluorinated gas and oxygen mixture; and (d) generatingat least one of the following using the acquired signal data: (i) a cineof free-breathing images of the lungs of the subject illustrating atemporal and spatial distribution of the perfluorinated gas in the lungspace and lungs of the subject to provide ventilation image data over atleast one respiratory cycle; (ii) at least one ventilation defect indexfor each of the right and left lungs; (iii) a ventilation defect indexmap showing a spatial distribution (pixel wise) of the lungs; (iv) avisual output to a display, the output including a time sequence ofairflow data of the subject with a plurality of MRI images positionedaligned with an acquisition time, in the time sequence; (v) aventilation pattern associated with a forced ejection volume; (vi) atleast one histogram associated with wash-in and/or wash-out of the gasmixture; (vii) at least one regional ventilation defect model showingintensity variation pixel to pixel; (viii) gas trapping images usingwash in and/or wash out ¹⁹F MRI signal data; (ix) a visual output of agraphic analysis fit to a lung model of ventilation wash-in and/orwash-out with a plurality of MRI images depicting functionalinformation; (x) a pattern of signal intensity depicting gas exchange tocapillary blood flow based on relaxation parameters (T1 and/or T2) andan impact of local oxygen concentration on the relaxation parameters;and (xi) at least one histogram associated with wash-in and/or wash-outof the delivered gas mixture.

Some embodiments generate a plurality of the generated images, maps,indexes, or data (per items i-xi).

The methods can include generating free breathing cine images of thelungs of the subject illustrating a temporal and spatial distribution ofthe perfluorinated gas in the lung space and lungs of the subject toprovide ventilation image data over at least one respiratory cycle(typically over a plurality of respiratory cycles and during at leastone of wash in and wash out of the gas mixture).

Optionally, the delivering step can be carried out using free-breathing,thereby allowing the subject to inhale and exhale the gas mixture over aplurality of respiratory cycles during the acquiring step.

In some embodiments, the methods can further include terminating thedelivering step, then allowing the subject to breathe room air whileremaining in the magnetic field of the MRI Scanner. The method thenacquires additional ¹⁹F MRI signal data gas and evaluates ventilationdata associated with gas trapping using the additionally acquired MRIsignal data.

The evaluating step may be carried out by generating images using theacquired MRI data illustrating a temporal and spatial distribution ofthe perfluorinated gas in the subject.

The perfluorinated gas mixture can include medical grade sulfurhexafluoride that is in a gaseous state at room temperature andpressure. The perfluorinated gas mixture can include a medical gradeperfluoropropane gas that is in the gaseous state at room temperatureand pressure. Other embodiments can include other medical gradeperfluorinated gases such as perfluoroethane, etc., although at thistime only sulfur hexafluoride and perfluoropropane are available inmedical grades.

In some embodiments, the method can also include directing the subjectto carry out a forced ejection volume breathing maneuver in one second(FEV1) of the gas mixture. Then the method can acquire MRI signal dataduring and/or after the forced ejection of the gas mixture and generateand evaluate a ventilation pattern based on the acquired MRI signal dataof the FEV procedure.

Optionally, the method may also include performing a spirometryprocedure of the subject while the subject is in a supine positionproximate in time to the positioning step.

In some embodiments, the method can include generating at least onehistogram of image intensity data using the acquired MRI signal data toidentify ventilation defects.

The acquiring step can include acquiring the ¹⁹F MRI signal data from aflexible or rigid lung coil positioned about the subject and the methodcan further include proton blocking the lung coil and substantiallyconcurrently or sequentially acquiring ¹H and ¹⁹F MR image signal data.

In some embodiments, the method can further include generating imagesusing respiratory cycle gating so that the acquiring step is performedover several respiratory cycles. The generating step can generate gatedcine images of a breathing lung of the patient with temporal andspatially distributed ventilation data in near-real time.

Other embodiments are directed to MRI systems. The systems include: (a)an MRI scanner comprising a magnet with a magnetic field and a body coilconfigured to obtain ¹H MRI signal data; (b) a flexible, semirigid orrigid lung coil configured to obtain ¹⁹F MRI signal data and sized andconfigured to reside about a patient; (c) an MRI scanner interface incommunication with the scanner and the lung coil, the interfacecomprising a proton blocking circuit; and (d) a gas delivery system. Thegas delivery system includes: (i) a gas mixture source comprisingperfluourinated gas in a level that is between about 20-79% and oxygengas in a level that is at least about 21%; (ii) a gas flow path incommunication with the gas mixture source comprising at least oneconduit extending from the gas mixture source to a dispensing memberresiding over, on or in a patient while the patient resides inside themagnetic field to deliver the gas mixture to the patient; and (iii)optionally, at least one oxygen sensor in communication with the gasmixture. In operation, the MRI system is configured to substantiallyconcurrently obtain ¹H and ¹⁹F MRI signal data of lungs and associatedlung airspaces of the patient and generate images showing a temporal andspatial distribution of the perfluorinated gas mixture in the lungs.

The system can optionally be configured to acquire the ¹H and ¹⁹F MRIsignal data while (a) the patient carries out free-breathing of the gasmixture for a plurality of respiratory cycles then (b) the patientcarries out free-breathing of room air for a plurality of respiratorycycles, and wherein the system is configured to generate cine images ofa breathing lung using the acquired signal data.

Some embodiments are directed to MRI systems that include: (a) an MRIscanner comprising a magnet with a magnetic field and a body coilconfigured to obtain ¹H MRI signal data; (b) a lung coil configured toobtain ¹⁹F MRI signal data and sized and configured to reside proximatea patient; (c) an MRI scanner interface in communication with thescanner and the lung coil, the interface comprising a proton blockingcircuit; and (d) a gas delivery system. The gas delivery system caninclude: a gas mixture source comprising perfluourinated gas in a levelthat is between about 20-79% and oxygen gas in a level that is at leastabout 20.5%; a gas flow path in communication with the gas mixturesource comprising at least one conduit extending from the gas mixturesource to a free-breathing dispensing member residing over, on or in apatient while the patient resides inside the magnetic field to deliverthe gas mixture to the patient; and at least one oxygen sensor incommunication with the gas mixture.

In operation, the MRI system is configured to obtain ¹H and ¹⁹F MRIsignal data of lungs and associated lung airspaces of the patient andgenerate images showing a temporal and spatial distribution of theperfluorinated gas in the lungs, wherein the system is configured toacquire the ¹⁹F MRI signal data while the patient carries out at leastone of (a) free-breathing of the gas mixture during equilibrium and washin and/or wash out for a plurality of respiratory cycles, (b) a singleor a plurality of breath holds of the gas mixture; and (c) an FEV of thegas mixture.

The system can be configured to generate at least one of the following:

(i) a cine of free-breathing images of the lungs of the subjectillustrating a temporal and spatial distribution of the perfluorinatedgas in the lung space and lungs of the subject to provide ventilationimage data over at least one respiratory cycle;

(ii) at least one ventilation defect index for each of the right andleft lungs;

(iii) a ventilation defect index map showing a spatial distribution(pixel wise) of the lungs;

(iv) a visual output to a display, the output including a time sequenceof airflow data of the subject with a plurality of MRI images positionedaligned with an acquisition time, in the time sequence;

(v) a ventilation pattern associated with a forced ejection volume;

(vi) at least one histogram associated with wash-in and/or wash-out ofthe gas mixture;

(vii) at least one regional ventilation defect model showing intensityvariation pixel to pixel;

(viii) gas trapping images using wash in and/or wash out ¹⁹F MRI signaldata;

(ix) a visual output of a graphic analysis fit to a lung model ofventilation wash-in and/or wash-out with a plurality of MRI imagesdepicting functional information;

(x) a pattern of signal intensity depicting gas exchange to capillaryblood flow based on relaxation parameters (T1 and/or T2) and an impactof local oxygen concentration on the relaxation parameters; and

(xi) at least one histogram associated with wash-in and/or wash-out ofthe delivered gas mixture.

The MRI system can be configured to substantially concurrently obtainthe obtain ¹H and ¹⁹F MRI signal data of the lungs. The system caninclude an image analysis circuit that is configured to electronicallyterminate the gas delivery and allow the patient to breathe room air fora plurality of respiratory cycles.

Still other embodiments are directed to MRI systems that include: (a) anMRI scanner having a control console in a first room and a magnet with amagnetic field in a scan room; and (b) a gas delivery system. The gasdelivery system includes: (i) a pressurized container of a gas mixturecomprising perfluorinated gas in a level that is between about 20-79%and oxygen gas in a level that is at least about 21%; (b) a gas flowpath in communication with the gas mixture source comprising at leastone conduit and at least one flexible bag extending from the containerto a dispensing member while the patient resides inside the magneticfield; and (c) optionally, at least one oxygen sensor in communicationwith the gas mixture in the gas flow path. In operation, the MRI systemis configured to obtain ¹⁹F MRI signal data and generate images showinga temporal and spatial distribution of the perfluorinated gas in thelungs.

The system can optionally be configured to acquire the ¹H and ¹⁹F MRIsignal data while (a) the patient carries out free-breathing of the gasmixture for a plurality of respiratory cycles, then (b) the patientcarries out free-breathing of room air for a plurality of respiratorycycles, and wherein the system is configured to generate cine images ofa breathing lung using the acquired signal data.

Still other embodiments are directed to gas delivery systems for an MRIsystem. The gas delivery system includes: (a) a medical grade gasmixture source of perfluorinated gas and oxygen gas; (b) a mouthpieceand/or mask residing downstream of the gas mixture source configured toreside inside a magnetic field of the MRI system; and (c) a flow pathextending from the gas mixture source to the mouthpiece and/or mask. Theflow path includes a first Douglas bag in fluid communication with thegas mixture source and may include a first spirometer filter residingdownstream of the first Douglas bag.

The gas delivery system may optionally also include a one-way valve incommunication with the mouthpiece or mask residing downstream of thefirst spirometer filter, a second spirometer filter residing downstreamof the mouthpiece or mask, and a second Douglas bag residing downstreamof the second spirometer filter whereby a patient can passively intakeand exhale the gas mixture.

The system can include a display in communication with the MRI scannerand a respiratory cycle gating circuit and an image analysis circuit incommunication with the MRI scanner. The MRI system can be configured togenerate gated free-breathing cine images with image data registered toa respiratory cycle using ¹⁹F image data acquired over a plurality ofpatient respiratory cycles, and wherein the display is configured topresent the gated cine images in near real-time showing the lungs of thepatient with temporal and spatially distributed ventilation dataassociated with the ¹⁹F image data.

The gas flow path can include an inspire gas flow path and an expire gasflow path, the system further comprising a first pneumotachometerresiding in the inspire gas flow path and a second pneumotachometerresiding in the expire gas flow path, and wherein the respiratory gatingcircuit is configured to use pneumotachometer data for respiratorygating input.

The system can include an image analysis circuit that is configured toregister ¹⁹F MRI lung images to a set of ¹H MRI lung images of thesubject, create lung masks from the ¹H MRI images, apply the createdmasks to the registered ¹⁹F images, then extract summary parameters fromthe ¹⁹F image data to assess ventilation defects. The summary parameterscan be extracted by volume and slice and include at least one of pixelintensity, pixel count, histogram, summary statistics and 2-D shapefactors.

The system can include a gas chamber in fluid communication with anexpire portion of the gas flow path positioned upstream of a Douglas bagfor gas capture. The gas chamber can be in communication with a chemicalanalyzer configured to analyze oxygen and carbon dioxide content insubstantially real time.

The system can include a display and an image analysis circuit incommunication with the MRI Scanner, the image analysis circuitconfigured to generate an overlay presentation of patient airflow dataover time aligned with a plurality of MRI images taken at differentpoints in time including inspire and expire breath-hold images of air,wash-in and wash out images of the perfluorinated gas mixture andfree-breathing perfluorinated cine MRI images.

Still other embodiments are directed to a gas delivery system for an MRIsystem. The gas delivery systems include: (a) a medical grade gasmixture source of perfluorinated gas and oxygen gas; (b) a mouthpieceand/or mask residing downstream of the gas mixture source configured toreside inside a magnetic field of the MRI system; and (c) an inspireflow path extending from the gas mixture source to the mouthpiece and/ormask. The flow path can include: a first Douglas bag in fluidcommunication with the gas mixture source; and a first spirometer filterresiding downstream of the first Douglas bag. The gas delivery systemcan be a passive system that allows a patient to “breath-hold” andfreely breathe the gas mixture.

The gas delivery system can also include enclosed expire gas flow pathresiding downstream of the mouthpiece or mask. The gas delivery systemcan also include: a one-way valve in communication with the mouthpieceand/or mask residing downstream of the first spirometer filter; a secondspirometer filter residing downstream of the mouthpiece and/or mask inthe expire gas flow path; and a second Douglas bag with a larger sizethan the first Douglas bag residing downstream of the second spirometerfilter.

The delivery system can include an enclosed expire gas flow pathresiding downstream of the mouthpiece or mask, a first pneumotachometerin fluid communication with the inspire gas flow path; a secondpneumotachometer in fluid communication with the expire gas flowpathmask; at least one pneumotachometer recorder in communication withthe first and second pneumotachometers; a gating circuit interface incommunication with the at least one recorder configured to provide MRIrespiratory gating input; a gas chamber in the expire gas flow pathupstream of a Douglas gas recovery bag; and a gas analyzer incommunication with the gas chamber configured to analyze oxygen andcarbon dioxide content of gas in the chamber.

Still other embodiments are directed to cines of free-breathing ¹⁹F MRIimages showing breathing lungs with a temporal and spatial distributionof perfluorinated gas associated with a ventilation pattern.

Yet other embodiments are directed to at least one right lungventilation defect index and at least one left lung ventilation defectindex, wherein the respective at least one index is determined based onMRI pixel signal intensity to thereby provide a patient-specific measureof lung function.

Additional embodiments are directed to a regional ventilation defectgraph showing right and left lung ventilation of ¹⁹F pixel signalintensity of perfluorinated gas in a subject's lungs over a defined timewith signal intensity at the defined time used to identify a ventilationdefect for each of a right and left lung of the subject.

Other embodiments are directed to regional ventilation indexes and/ormaps of pixel variation in the lungs associated with ¹⁹F signal data.

Yet other embodiments are directed to a cine of MRI images showingbreathing lungs with a temporal and spatial distribution ofperfluorinated gas associated with a ventilation pattern.

Additional embodiments are directed to pressurized canisters of amedical grade gas mixture comprising at least about 21% oxygen andbetween about 20% to about 79% inert pefluorinated gas.

The canister may also include a temperature sensor on the canister forindicating whether the canister has been exposed to a temperature below5° C.

Some embodiments are directed to a trifunctional medical grade gascomposition for administration to a human patient, comprising about 21%oxygen gas and between about 20% to about 78% inert perfluorinated gas,and the balance anesthesia gas.

Embodiments of the invention are directed to systems and methods ofimaging a spatial distribution of a perfluorinated gas by nuclearmagnetic resonance spectrometry, which include detecting a spatialdistribution of at least one perfluorinated gas by NMR spectrometry(e.g., MRI scanner) and generating a representation of the spatialdistribution of the perfluorinated gas. The representation can begenerated in 3-D volume or 2-D Multislice or projection images with anadditional temporal dimension related to the ventilation pattern of thegas including the inhalation and exhalation phase. The perfluorinatedgas may be imaged according to the invention in chemical or biologicalsystems, preferably in a human or animal subject or organ system ortissue thereof.

Also, apparatus for nuclear magnetic resonance imaging of the spatialdistribution of the perfluorinated gas includes means for imaging aperfluorinated gas by NMR spectrometry and means for providing and/orstoring imageable quantities of a perfluorinated gas as well as thedelivery of the gas to the subject.

Further, a medical composition may include a trifunctional gas mixtureincluding a medical grade (inert) perfluorinated gas, medical gradeoxygen and a third gas which may include an anesthetic gas or otherrelevant support gas (e.g., He).

Embodiments of the invention can employ a mathematical model that can beused to interrogate the image data and generate a map of regionalventilation function.

It is noted that aspects of the invention described with respect to oneembodiment, may be incorporated in a different embodiment although notspecifically described relative thereto. That is, all embodiments and/orfeatures of any embodiment can be combined in any way and/orcombination. Applicant reserves the right to change any originally filedclaim or file any new claim accordingly, including the right to be ableto amend any originally filed claim to depend from and/or incorporateany feature of any other claim although not originally claimed in thatmanner. These and other objects and/or aspects of the present inventionare explained in detail in the specification set forth below.

The foregoing and other objects and aspects of the present invention areexplained in detail herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic illustration of an MRI system with a gas deliverysystem according to embodiments of the present invention.

FIG. 1B is a schematic illustration of an MRI system with an alternategas delivery system according to embodiments of the present invention.

FIG. 1C is a schematic illustration of an MRI system and gas deliverysystem similar to those shown in FIGS. 1A and 1B but with an imaginggateway/interface according to embodiments of the present invention.

FIG. 2A is a schematic illustration of another gas delivery systemaccording to embodiments of the present invention.

FIG. 2B is a schematic illustration of yet another gasdelivery/monitoring system according to embodiments of the presentinvention.

FIG. 3 is a schematic illustration of another exemplary gas deliverysystem according to embodiments of the present invention.

FIG. 4A is an illustration of a lung imaging coil jacket incommunication with a gateway interface and blocking network power supplyaccording to embodiments of the present invention.

FIG. 4B is a schematic illustration of an imaging system that cantemporally switch between the PFx and O2 gas mixture delivery andalternate gas delivery (e.g. room air, 100% O2, etc) according toembodiments of the present invention.

FIGS. 5A-5C are graphs of signal versus flip angle, each graph using aTR of 10 ms and a TE of 1 ms (all other T numbers are also shown in msunits). FIG. 5A is a signal plot of lung water. FIG. 5B is a signal plotof SF6 and FIG. 5C is a signal plot of PFP.

FIG. 6 is a flow chart of operational steps that can be used to carryout embodiments of the present invention.

FIG. 7 is a schematic illustration of a data processing system that canbe used to carry out embodiments of the present invention.

FIG. 8 is a reproduction of in vivo images 3D GRE (Gradient refocusedecho) VIBE (Volumetric Interpolated Breath-hold Examination) of PFP of apair of human lungs using a perfluorinated gas and oxygen gas mixture ina single breath hold.

FIG. 9 is a panel of images of a patient's lung. The left images are ¹H(base) images, the right images are PFx (match) images and the centerimages are 3D fusion images of ¹H and PFx (typically shown color-coded).The top row of images corresponds to transverse slices, the center rowof images corresponds to coronal slices and the bottom row of imagescorresponds to sagittal slices.

FIG. 10 is a image of the lungs showing regional lung morphometricinformation using 1H image data to demonstrate coverage of the lungsaccording to embodiments of the present invention.

FIG. 11 is a visualization of a series of lung images obtained using PFxgas mixtures showing regional data of lung ventilation and/or function(e.g. ventilation defects, deficiencies, gas trapping and the like)(shown in panels C-6 through C-20) using PFx and oxygen gas mixturesaccording to embodiments of the present invention.

FIGS. 12A and 12B are examples of time-series images of a “leakingglove” phantom housed in an acrylic sphere which allowed PFx to leakinto the sphere via a small hole in the glove. The images illustratedata analyzed spatially to show contrast between differentconcentrations of PFx analogous to ‘gas trapping’ according toembodiments of the present invention.

FIGS. 13A and 13B illustrate two ROIs (Region of Interests) using theleaking glove phantom. FIG. 13A shows two regions of interest ‘grown’using a seeded approach while 13B shows a region of the entire ‘object’.

FIG. 14 is a graph of occurrences versus intensities of pixels/voxels ofthe object illustrating that the intensity data/concentrationdifferences can be analyzed numerically according to embodiments of thepresent invention. This shows a ‘modal’ distribution of intensitiesanalogous to gas trapping.

FIG. 15 is a flow chart of exemplary image analysis steps that can beused to identify ventilation defects and trapped gas volume according toembodiments of the present invention.

FIG. 16 is a schematic illustration of an image analysis protocol thatcan be used to identify ventilation defects or abnormalities usingextracted summary parameters according to embodiments of the presentinvention.

FIGS. 17A and 17B are charts of examples of extracted summary parametersin slices of an image volume according to embodiments of the presentinvention.

FIG. 18 is a graph of PFx signal over time for regional analysis ofventilation defects according to embodiments of the present invention.

FIG. 19 is a screen shot of an example of a overlay plot ofpneumotachometer output over time with interposed MRI images at notedtimelines according to embodiments of the present invention.

FIGS. 20A and 20B are images and associated graphs of pixel count versusPFx pixel intensity using a histogram ventilation defect analysis fordifferent patients according to embodiments of the present invention.Notably, both of the patients have substantially the same FEV1 value butdifferent defects.

FIG. 21 is a schematic of a standardized compartment model of the lungsthat can be used to identify lung ventilation defect indexes fordifferent patients according to embodiments of the present invention.

FIG. 22 is a set of images taken at sequential times (and incrementalgas dose) for wash-in kinetic analysis of ventilation defect severityfollowed by wash-out after switching to room air.

FIG. 23 is an example of a graph, mean signal over time (based on aseries of images) of wash-in and wash out from a region of interestassociated with images shown in FIG. 22.

DETAILED DESCRIPTION

The present invention will now be described more fully hereinafter withreference to the accompanying figures, in which embodiments of theinvention are shown. This invention may, however, be embodied in manydifferent forms and should not be construed as limited to theembodiments set forth herein. Like numbers refer to like elementsthroughout. In the figures, certain layers, components or features maybe exaggerated for clarity, and broken lines illustrate optionalfeatures or operations unless specified otherwise. In addition, thesequence of operations (or steps) is not limited to the order presentedin the figures and/or claims unless specifically indicated otherwise. Inthe drawings, the thickness of lines, layers, features, componentsand/or regions may be exaggerated for clarity and broken linesillustrate optional features or operations, unless specified otherwise.Features described with respect to one figure or embodiment can beassociated with another embodiment of figure although not specificallydescribed or shown as such.

It will be understood that when a feature, such as a layer, region orsubstrate, is referred to as being “on” another feature or element, itcan be directly on the other feature or element or intervening featuresand/or elements may also be present. In contrast, when an element isreferred to as being “directly on” another feature or element, there areno intervening elements present. It will also be understood that, when afeature or element is referred to as being “connected”, “attached” or“coupled” to another feature or element, it can be directly connected,attached or coupled to the other element or intervening elements may bepresent. In contrast, when a feature or element is referred to as being“directly connected”, “directly attached” or “directly coupled” toanother element, there are no intervening elements present. Althoughdescribed or shown with respect to one embodiment, the features sodescribed or shown can apply to other embodiments.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention. Asused herein, the singular forms “a”, “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. It will be further understood that the terms “comprises”and/or “comprising,” when used in this specification, specify thepresence of stated features, steps, operations, elements, and/orcomponents, but do not preclude the presence or addition of one or moreother features, steps, operations, elements, components, and/or groupsthereof. As used herein, the term “and/or” includes any and allcombinations of one or more of the associated listed items.

It will be understood that although the terms “first” and “second” areused herein to describe various components, regions, layers and/orsections, these regions, layers and/or sections should not be limited bythese terms. These terms are only used to distinguish one component,region, layer or section from another component, region, layer orsection. Thus, a first component, region, layer or section discussedbelow could be termed a second component, region, layer or section, andvice versa, without departing from the teachings of the presentinvention. Like numbers refer to like elements throughout.

Unless otherwise defined, all terms (including technical and scientificterms) used herein have the same meaning as commonly understood by oneof ordinary skill in the art to which this invention belongs. It will befurther understood that terms, such as those defined in commonly useddictionaries, should be interpreted as having a meaning that isconsistent with their meaning in the context of the specification andrelevant art and should not be interpreted in an idealized or overlyformal sense unless expressly so defined herein. Well-known functions orconstructions may not be described in detail for brevity and/or clarity.

In the description of the present invention that follows, certain termsare employed to refer to the positional relationship of certainstructures relative to other structures. As used herein, the term“front” or “forward” and derivatives thereof refer to the direction thatthe gas mixture flows during use toward a patient (and where capturedupon exhale, then away from a patient); this term is intended to besynonymous with the term “downstream,” which is often used inmanufacturing or material flow environments to indicate that certainmaterial traveling or being acted upon is farther along in that processthan other material. Conversely, the terms “rearward” and “upstream” andderivatives thereof refer to the direction opposite, respectively, theforward or downstream direction.

The term “circuit” refers to an entirely software embodiment or anembodiment combining software and hardware aspects, features and/orcomponents (including, for example, a processor and software associatedtherewith embedded therein and/or executable by, for programmaticallydirecting and/or performing certain described actions or method steps).

The term “map” refers to a rendered visualization of one or moreselected parameters, conditions, or behaviors of pulmonary (lung) tissueor airway using MR image data, e.g., the map is a rendered partial orglobal anatomical map that shows ventilation and/or perfusioninformation in a manner that illustrates relative degrees or measures offunction, typically using different colors, opacities and/orintensities.

The actual visualization can be shown on a screen or display so that themap or ventilation information images and/or anatomical structure is ina flat 2-D and/or in a 2-D projection image in what appears to be 3-Dvolumetric images with data representing features with different visualcharacteristics such as with differing intensity, opacity, color,texture and the like. A 4-D map can either illustrate a 3-D or 2-Dprojection image of the lung with movement (e.g., wall movementassociated with a respiratory cycle) or a 3-D map with ventilationinformation during inhale and/or exhale.

The term “5-D visualization” means a 4-D visualization image (e.g., adynamic/moving 3-D or 2-D projection image of a breathing lung) withfunctional (ventilation) spatially encoded or correlated informationshown on the moving visualization.

The term “programmatically” means that the operation or step can bedirected and/or carried out by a digital signal processor and/orcomputer program code. Similarly, the term “electronically” means thatthe step or operation can be carried out in an automated manner usingelectronic components rather than manually or using any mental steps.

The terms “MRI scanner” or MR scanner” are used interchangeably to referto a Magnetic Resonance Imaging system and includes the high-fieldmagnet and the operating components, e.g., the RF amplifier, gradientamplifiers and processors that typically direct the pulse sequences andselect the scan planes. Examples of current commercial scanners include:GE Healthcare: Signa 1.5 T/3.0 T; Philips Medical Systems: Achieva 1.5T/3.0 T; Integra 1.5 T; Siemens: MAGNETOM Avanto; MAGNETOM Espree;MAGNETOM Symphony; MAGNETOM Trio; and MAGNETOM Verio. As is well known,the MR scanner can include a main operating/control system that ishoused in one or more cabinets that reside in an MR control room whilethe MRI magnet resides in the MR scan suite. The control room and scanroom can be referred to as an MR suite and the two rooms are generallyseparated by an RF shield wall.

The term “cine” refers to a series of images shown dynamically, e.g., abreathing lung in motion during a respiratory cycle or cycles, and istypically carried out by looping image slices of a stack of images ofthe lungs and/or lung airways to form a dynamic series of images at acertain frame rate (typically stated in frames per second “fps”). Theframe rate may be adjusted by a user to have a faster or lower speed forease of review of lung function or the like.

The term “MRI compatible” means that the so-called component(s) issuitable for use in an MRI environment and as such is typically made ofa non-ferromagnetic MRI compatible material(s) suitable to reside and/oroperate in or proximate a conventional medical high magnetic fieldenvironment. The “MRI compatible” component or device is “MR safe” whenused in the MRI environment and has been demonstrated to neithersignificantly affect the quality of the diagnostic information nor haveits operations affected by the MR system at the intended use position inan MR system. These components or devices may meet the standards definedby ASTM F2503-05. See, American Society for Testing and Materials (ASTM)International, Designation: F2503-05. Standard Practice for MarkingMedical Devices and Other Items for Safety in the Magnetic ResonanceEnvironment. ASTM International, West Conshohocken, Pa., 2005.

The term “high-magnetic field” refers to field strengths above about 0.5T, typically above 1.0 T, and more typically between about 1.5 T and 10T. Embodiments of the invention may be particularly suitable for 3.0 Tsystems, or higher field systems such as future commercial systems at4.0 T, 5.0 T, 6.0 T and the like, but can also be implemented at 1.5 T.

Generally stated, perfluorinated (which can be abbreviated by the term“PFx”) gases can be used as imaging agents during MRI to allow datacapture of regional ventilation information. As noted above, the term“perfluorinated gas” (“PFx” gas) refers to inert medical grade gasesderived from common organic perfluorocarbon or other perfluorinatedcompounds with the hydrogen atoms replaced with fluorine atoms. Formedical administration to humans and animals, the PFx gas should beformulated as a medical grade gas with toxic chemicals/elements removedor present at levels defined as acceptable for medical use and withmicrobial limits in compliance with (and testing performed to meet)regulatory microbe and medical grade guidelines, such as the thosestated in USP Chapter 1111 as issued by the United States Food and DrugAdministration in 2009 and USP 61 and 62. Examples of suitable PFx gasesinclude sulfur hexafluoride gas (SF₆) and perfluoroalkanes, such as, butnot limited to, Perfluoropropane (“PFP”, also known as C₃F₈) that aregaseous at room temperatures and pressures. The nominal roomtemperatures are believed to be between about 20-25° C. and 1 atm (sealevel) but the gas mixture can be used at lower and higher temperaturesand a range of pressures, but below a pressure that can cause the gas toliquefy so as to maintain the composition of the gas. Other PFx gasesmay also be suitable such as perfluoroethane, perfluorocyclobutane, andperfluoromethane. The perfluorinated gas is at least thermally orequilibrium polarized by a static magnetic field generated by a magnetthat is large enough to contain the subject “S”.

Embodiments of the invention can generate a representation of theperfluorinated gas spatial distribution in the lungs/airways thatincludes at least one dimension, but preferably 2 or 3 dimensions of thespatial distribution. In addition, the representation can be provided ina fourth dimension (temporal) related to the ventilation pattern of thegas including the inhalation and exhalation phase.

Embodiments of the invention use conventional ‘thermally’ polarizedperfluorinated gases (PFx) mixed with oxygen for use as inhaled inertMRI contrast agents to image lung function, e.g., ventilation andvarious ventilation defects. These PFx agents attain a relatively highthermal polarization exceptionally quickly, which, coupled with a large¹⁹F MR signal (magnetic moment) and molecular symmetry, allows imagingventilation with a quality similar to that of hyperpolarized ¹²⁹Xe MRI,but at lower cost and with reduced technical complexity. SF6 has a T1 ofabout 2 ms while perfluoropropane has a T1 of about 20 ms. Thus, becauseof the different physicochemical properties and/or T1's, one or theother may be more suitable for different breathing patterns. The PFxgases can allow for rapid image acquisition with near real-time imagingof ventilation dynamics. The term “near real-time” means that theventilation dynamic images can be generated while a patient is in theMRI scanner suite, typically within about 30 seconds to about 5 minutesfrom initial signal acquisition. An entire lung evaluation image sessioncan be relatively short, typically between about 5-30 minutes, and moretypically between about 10-15 minutes. The images can be obtained in a(gated) cine mode with free-breathing delivery.

It is also contemplated that from a ventilation information viewpoint,embodiments of the present invention can evaluate the MR image data fromthe PFx gas mixture to assess and/or measure gas trapping and can allowa temporal domain analysis of gas trapping that is not easily obtainedwith current imaging strategies. In addition, or alternatively,sequential breath-hold images or time gated images can identify wash-inand wash-out information. These embodiments can be used to grade theseverity of the ventilation defects an approach also not easily obtainedwith current imaging strategies. Also, due to the relatively optimumrelaxation conditions due to dominance of spin rotation relaxation onthese agents and the ability to obtain a signal from the incoming gasdelivery system, the contemplated systems may provide a morequantitative analysis and display of lung ventilation and/or functionalinformation. Changes in signal intensity of the PFx mixtures aresensitive to local oxygen concentration. In some embodiments, anestimate of oxygen gas exchange (perfusion) can be accomplished using T1weighed images, ratio or subtraction images or calculated T1 images. Itis noteworthy that these embodiments can employ a PFx agent with longerT1 relaxation times, e.g., PFx agents having a T1 above about 10 ms,such as, for example, perfluoropropane.

Embodiments of the invention may be used with “free-breathing” deliveryof the PFx gas mixture in contrast to breath-hold methodologies. Theterm “free-breathing” means that the subject is able to passively inhaleand exhale the gas mixture in a substantially normal breathing orrespiratory cycle without the requirement of “breath-hold” or aventilator or regulated gas delivery system. It is noted that“free-breathing” may be carried out by directing the subject to inhaleor exhale at a different rate, e.g., with faster or lower respiratorycycles, shallow or deep breaths or a forced ventilation breath (e.g.,FEV1/FEC). The respiration can be via the nose and/or mouth but does notrequire that a patient actually hold his or her breath during theimaging. It is believed that the free-breathing delivery can provideimproved accuracy in information regarding actual lung ventilation inthe human lung(s) where a combination of convection and diffusionprovide the ventilation dynamics over several breaths as the tidalvolume is roughly ⅙th of the total volume. It is possible thatventilation defects found with other conventional (e.g., breath-hold)methods may not be accurate. In addition, “free-breathing” may make thesystem particularly suitable for patients with impaired breathingfunction and/or for pediatric use.

The lung contains three primary components: air (during normalbreathing), blood and tissue. Generally stated, the structural andphysiologic arrangement of these components provides for gas exchangeand (typically) efficient resistance to the movement of air and blood.Also, the lung can provide for removal of particulate matter in inspiredair by a specialized transport mechanism referred to as mucocilliaryclearance (a homeostatic process). An example of a model used todescribe geometric and/or morphologic changes can be obtained from R.Weibel, Morphometry of the Human Lung, Spinger-Verlag, Berlin, (1963),pp. 1-151; and The Physiology of Breathing, Grune & Stratton, 1977, NewYork, pp. 60-79; 173-232. It is contemplated that embodiments of theinvention can generate images with ventilation data/patterns showingmorphology and function based on the temporal and spatial distributionof the ¹⁹F (and ¹H) signals in the lung space and tissue. It is notedthat 19F is used interchangeably with the superscript version ¹⁹F and 1His also used interchangeably with its superscript version ¹H in thisdocument.

Turning now to the figures, FIG. 1A illustrates a system 10 with an MRIscanner 20 and a gas delivery system 30. The MRI scanner 20 includes ahigh-field magnet 20M (typically in the scan room of the MRI suite). Themagnet is typically at least about a 3.0 T magnet, but embodiments ofthe system 10 may be used with a 1.5 T magnet or a magnet at otherhigher field strengths. The MRI scanner 20 includes a control console 21and a display 22. The display 22 can be integral with the console 21and/or may be provided in a clinician workstation to display images. Thescanner 20 can communicate with the body coil 23 typically included inthe magnet housing in the scan room via lead 25 to direct the pulsesequence and transmit receive operation as is known to those of skill inthe art.

The gas delivery system 30 includes a source 30 s of perfluorinated gas(“PFx”) and oxygen gas mixture 30 g. The oxygen gas is typicallyprovided in a normoxic amount, typically between about 20% and 21%, moretypically between 20.5% to about 21%. The oxygen level should bemaintained above 19.2%. Other gases may be included in the blend(mixture) as suitable for medical use. However, the PFx gas is typicallyprovided in an amount that is between about 20%-79% of the gas mixture,and more typically between about 40% to about 79%.

The gas delivery system 30 includes at least one conduit 33 (e.g.,typically flexible MRI compatible tubing) that extends from the source30 s to the delivery device 30 d located proximate the subject “S” inthe magnet 20M. The system 30 can include at least one valve 31 and flowregulator 32. The gas flow can be provided as a demand flow rate(controlled by the patient) or at suitable flow rates as is known tothose of skill in the art and may vary by patient size age or breathingcapacity.

The at least one conduit 33 can be provided as about a 15-50 mm diametertubing, typically about a 38 mm diameter tubing, and may be single-usedisposable. However, other size conduits may be used. Further, thesubject can be isolated from the system by a high efficiency spirometryfilter situated just after the delivery device 30 d. The delivery device30 d can be in any suitable form, typically a mask or mouthpiece.However, the delivery device 30 d can comprise an intubation tube asappropriate for a particular patient. The system 10 can include at leastone oxygen sensor 40 that can be placed along the gas delivery path. Anelectrical and/or optical lead can extend from the sensor to the oxygenlevel monitor 42. Alternately, the (non-destructive) oxygen sensorsystem may continuously sample the source gas 30 s using a pump systemand return the gas to the source. The sensor 40 may also communicatewith the monitor 42 wirelessly, e.g. Bluetooth.

As shown in FIG. 1A, the oxygen sensor 40 is placed proximate thedelivery device 30 d to confirm that the correct oxygen level is presentin the gas mixture just prior to delivery to a patient. This sensor 40can reside inside or outside of the magnet 20M. However, in otherembodiments, the sensor 40 can reside upstream of the delivery device,such as proximate the source 30 s. In other embodiments, a plurality ofoxygen sensors 40 (FIGS. 1B, 3) can be used to provide redundancy in theoxygen verification/monitoring system. In some embodiments, a pulseoximetry system, such as a finger tip pulse oximetry system (forexample, In Vivo MVS 3155 or the NONIN 7500FO) can also be used tomeasure patient oxygen saturation level (SpO2) (not shown) while thepatient is in position in the scanner bore. A small drop in oxygensaturation (SpO2 about 1-2%) may be expected, in particular ifbreathhold techniques are used. The SpO2 may be monitored for largerchanges which could determine if the study is to be terminated. Aminimum SpO2 can be set with an alarm feature on most oximetry systems.

The source 30 s can comprise two separate gas supplies, one for oxygenand one for PFx that can be mixed in situ at a clinical use site, suchas in real time or prior to the procedure, to provide the desired blendfor the procedure and monitor for and/or filter any undesired microbes.A monitor can include one or more lasers or other sensor(s) to confirmthe correct oxygen percentage is present. In such an embodiment, themicrobial levels can be determined on the source gases independently.

In other embodiments, the PFx gas and oxygen gas 30 g may be supplied asa pre-mixed gas at low pressure in a pressurized canister 30 c (FIG.2A). For example, an 8 inch diameter 52 inch canister of SF6 (at about79%) and O₂ (at about 21%) at 234 psig can provide about 472 liters ofthe SF₆ gas mixture. An 8 inch diameter 52 inch canister of PFP (atabout 79%) and O₂ (at about 21%) at 68 psig can provide about 136 litersof the gas mixture. Smaller (e.g., personal use) size canisters orlarger canisters may be used. Suitable medical grade gas mixtures can beobtained from Air Liquide, Scott Medical Products, Plumsteadsville, Pa.The source 30 s can be placed in the control room or in the scan room oreven outside the MR suite and flowably directed into the suite viadelivery lines. If placed in the scan room (inside the RF shield), thenaluminum or other suitable MRI-compatible material can be used to formthe canister or components of the system. The gases are supplied at lowpressure so that the dense gas component remains in the gaseous stateunder normal operating conditions of about 21 degrees C. or roomtemperature. Because both components are in the gaseous phase at thistemperature, the component ratio of the mix that is drawn out of thecylinder will remain constant.

Exposures to low temperatures should be avoided (store and use aboveabout 5° C./41° F. or, in some embodiments, above about 10° C./50° F.)as condensation of one of the components (namely, the SF₆ or C₃F₈) mayoccur, thereby disturbing the component ratio of the vapor phase. Insuch a situation, the gas cylinder can be warmed to room temperature and‘mixed’ by rotation of the cylinder and the concentration checked aspreviously described, particularly, the oxygen level by an oxygen sensor40. Thus, where pre-mixed pressurized gas sources are used, a lowtemperature indicator or sensor can be placed on or in the container 30c. The gas mixture is formulated to have a “dew point” of 0 degrees C.so that it will not condense above this temperature. The vapor pressureof PFP at 0 degrees C. is 60.41 psi and the vapor pressure of SF6 at 0degrees C. is 182.01 psi. To determine the overall pressure of themixture (at 0 degrees C.), the vapor pressure is divided by theconcentration of the mixture. Then this number can be multiplied by294/273 (degree Kelvin to degree C. conversion) to find the pressure at21 degrees C./70 degrees F.

For 79% PFP:60.41/0.79=76.46 psia@0° C.×294/273=82.35 psia@21° C.−14.7=67.65psig@21° C.For 79% SF6:182.01/0.79=230.39 psia@0° C.×294/273=248.11 psia@21° C.−14.7=233.41psig @21° C.

FIGS. 1A and 1B illustrate a display 22 configured with a user interface(UI) 22I. The display 22 can present a ventilation map or a display oflungs with regional ventilation information data. For example, theventilation map can comprise a 3-D anatomical map of at least a regionof the lung with spatially correlated intensity data associated with,for example, gas trapping and/or wash in and wash out of a PFx gas,taken from MR image data incorporated therein. The UI 22I may also beconfigured to display intensity histograms (pixel intensity over time),typically correlated to a lung/ventilation defect, a ventilation defect(numeric or alphanumeric) index and the like. The UI 22I can beconfigured to allow a user to zoom, crop, rotate, or select views of themap. The UI 22I can include multiple different GUI (Graphic User Input)controls for different functions and/or actions. The GUI controls mayalso be a toggle, a touch screen with direction sensitivity to pull in adesired direction or other graphic or physical inputs.

The UI 22I can include a list of user selectable images associated withthe procedure that can be selected for viewing by a user. The UI 22I canalso include GUI controls that allow a user to select two or more of theimages, typically maps, to be shown together (overlaid and registeredsuch as fused ¹H and ¹⁹F lung images). As shown in FIG. 1C, the display22 can be provided in or associated with a stand alone workstation 60 incommunication with the MRI scanner 20. The workstation 60 can include acircuit (e.g., ASIC and/or processor with software) that includes orexecutes part or all of the computer readable program code forgenerating the ventilation map(s), ventilation images with regionalventilation information, and/or cines of a breathing lung showing lungfunction. However, part or all of the circuit can reside in the MRIscanner 20 or in one more remote processors.

Optionally, an MRI scanner interface 66 may be used to allowcommunication between the workstation 60 and the scanner 20. Theinterface 66 and/or circuit may be hardware, software or a combinationof same. The interface 66 and/or circuit may reside partially or totallyin the scanner 20, partially or totally in the workstation 60, orpartially or totally in a discrete device therebetween. The display 20can be configured to render or generate near real-time visualizations ofthe target anatomical space/lungs using MRI image data.

FIG. 1B illustrates that the system 10′ can include an MRI compatibleanesthesia delivery system 38 that provides an anesthesia (such as ageneral anesthesia) along with the gas mixture from the source 30 s.Where this type of anesthesia-based system is used, the oxygen can be ata level that is between about 20-21%, the anesthesia gas can be at alevel between about 5-20%, typically about 15%, and the PFx gas can beat a level of between about 75%-59%.

FIG. 1B also illustrates that the system 10′ can include a patientmonitor 39 which can monitor oxygen level in the general anesthesiadelivery gas 38 g as well as other patient vital signs. The patientmonitor 39 can be separate from or integral with the anesthesia deliverysystem 38 monitoring system.

FIGS. 1B and 1C also illustrate that the system 10, 10′ can also includea ¹⁹F transmit/receive lung coil 28. The coil 28 is tuned to a selectedfrequency range associated with ¹⁹F for the MRI field strength in use(e.g., about 115 MHz for a 3 T system) and positioned on asubject/patient to transmit the excitation pulses and to detectresponses to the pulse sequence generated by the MRI unit. The coil 28can be a quadrature coil in a relatively flexible wrap-around (vest- orjacket-like) configuration (FIG. 4A) with conductors positioned on boththe front and back of the chest. Alternately, a semi-rigid or rigid coilconfiguration is also possible using ‘birdcage’ geometry, ‘phased array’geometries and or parallel imaging geometries. A suitable (prototype)coil is made by Clinical MR Solutions, Brookfield, Wis. In otherembodiments, the coil 28 can be a multi-piece (e.g., two-piece) coilthat provides the front and back (top and bottom) conductors for signaltransmit/receive (Tx/Rx). Different coil sizes may be used for differentsize patients, e.g., S, M, L, child and the like, each having differentradial and/or longitudinal extension and/or fit. Examples of other coiltypes known to those of skill in the art include a bird cageconfiguration, a Helmholtz pair, and a phased array.

Embodiments of the present invention use multifrequency imaging, e.g.,concurrent ¹H and ¹⁹F imaging. Thus, the system 10 can be configured toscan using ¹H imaging either with the body coil 23 (the ¹⁹F coil 28 canbe ¹H blocked) or with a two frequency array or other coil andoperational arrangement with the lung coil 28 in position. Otherembodiments of the present invention can use parallel imaging to improvethe speed of acquisition or decrease the specific absorbed radiation(SAR) of the acquisition.

FIG. 1C illustrates that the system 10 can include an interface/gateway50 with a blocking circuit 50C that can be in communication with thecoil 28. The coil 28 is actively proton-blocked to allow ¹H imagingthrough the coil 28 or coil 23 while the coil 28 is in place on thesubject. The MR scanner can transmit either 1H or 19F frequencies in oneembodiment of the invention and in other embodiments may alternate thefrequencies in real time or simultaneously transmit 1H and 19Ffrequencies for image formation and acquisition. In all embodiments the19F coil will be statically or dynamically disabled during the 1Htransmission.

The interface/gateway 50 can be connected to the coil 28 via lead 27 ₁and to a channel associated with the scanner via lead 27 ₂. Theinterface/gateway 50 can reside in the control room or in the scan room.The gateway/interface 50 with blocking circuit 50 c will be discussedfurther below.

FIG. 2A illustrates another example of a delivery system 30. As shown,the system 30 includes a pressurized canister 30 c with the PFx/O₂ gasmixture 30 g. The canister 30 c can include a flow regulator 33 andvalve 31. The canister 30 c can also include a temperature sensor 36 toconfirm that the canister 30 s has not been exposed to elevatedtemperatures so that the mixture is suitable for dispensing. The sensor36 can be a sensor that changes color if exposed to a temperature abovethe defined threshold (e.g., green is “good” and red is “bad”). Thesensor 36 can include or be in communication with an electronic monitor36 m with a power source (such as an on-board battery) that can providean audio and/or visual alert if the canister 30 c has been exposed to anundesired temperature (e.g., a temperature below about 5° C./41° F.).The electronic monitor 36 m can also include a circuit that can receiveand hold data indicative of the date/time filled and store temperaturereadings taken at desired intervals, such as, for example, every 10seconds to every 30 minutes, typically every 1-10 minutes. Theelectronic monitor 36 m can include a circuit with memory that holds thetemperature information (and lot number, supplier and/or other relevantgas information) and the memory and/or monitor can form part of thepatient record. If, during or after filling the canister 30 c with thegas mixture 30 g, the canister 30 c has been exposed to an undesiredtemperature, the length and date of the over-exposure can be identifiedto allow a user to address the shipment/handling issue. In such asituation, the gas cylinder can optionally be warmed to room temperatureand ‘mixed’ by rotation of the cylinder and the concentration checked aspreviously described by an oxygen sensor 40.

As shown in FIG. 2A, the system 30 can include a conventional Douglasbag arrangement with continuous monitoring of the source gas 30 g oxygenlevel using oxygen analyzer 42 with a pump in fluid communication with asampling supply line 43 and return line 45. Thus, the system 30 canprovide a continuous (circulating) sampling system of the gas mixture 30g.

As shown in FIG. 2A the system 30 can include a flow path 33 with amicrobe filter 51 (such as a 0.22 micron millipore filter) residingbetween an intake-side Douglas bag 55 and a high-efficiency spirometerfilter 53. The Douglas bag 55 can be between about 1-200 liters and istypically about a 25 liter bag. The high efficiency spirometer filtercan provide low flow resistance and suitable a bacterial & Viral filter,e.g., a bacterial filtration efficiency of about 99.9999%. In thisexample, the microbe filter is a Cole Parmer, Vernon Hills, Ill., NylonSterile Syringe Filters; Pore Size; 0.20, microns Item#: EW-02915-04.The spirometer filter can include a Resp Therapy Filter Item#: MQ 303from Vacumed, Ventura, Calif. The oxygen analyzer can include theOxigraf Oxygen Analyzer Item #: 07-0006. The one way valves can beobtained from Vacumed (Item# R5010). The non-rebreathing T-valve can beobtained from Vacumed Item#1464. Other components such as the tubing,Douglas Bags and connectors can also be obtained from Vacumed.

The flow path 33 can also include a mouthpiece 30 d in communicationwith a one-way breathing valve 35. The inhale gas flows into themouthpiece 30 d. The mouthpiece 30 d can include or be in communicationwith a (non-rebreathing) “Y” valve and/or a one-way valve 35 to allowfor free-breathing. The system 30 can also optionally include a laseroxygen level sensor 40 (FIGS. 1A-1C) downstream of the spirometer filter53. The system 30 can also include another (high efficiency) spirometerfilter 53 residing downstream of the mouthpiece 30 d in communicationwith the exhale Douglas bag 56 (where used). The exhale-side Douglas bag56 can be larger than the inhale-side bag 55, typically at least fourtimes as large, such as, for example, about 150 liters. The tubingforming the flow path 33 and the valve 35 and mouthpiece 30 d can besingle-use disposable.

The system can include a three-way pneumatically controlled valve 44 vconnected to the pneumatic control 44 in the control room (FIG. 2B).

FIG. 2B illustrates a system 30′ similar to that shown in FIG. 2A.Features described with the above system 30 can be included with thissystem 30′ and features described with this system 30′ can be used withthe above system 30 although not specifically described or showntherewith. Further, not all components shown with either system 30, 30′are required for either one.

The system 30′ shown in FIG. 2B can also include an MRI compatiblepneumotachometer 34 positioned along the intake flow path 33 i with aconnecting line 34 l extending to an amplifier and data recorder 34A.The amplifier/recorder 34A typically resides in the MR control room butmay also reside offsite or even in the magnet room (with propershielding). The system 30′ may also include An MRI compatiblepneumotachometer 134 along the outgoing flow path 33 o. Thispneumotachometer 134 may also include a line 134 l that connects to anamplifier/data recorder 134A. Although shown as two pneumotachometers34, 134, these may be integrated into a single device. The recorder 134Amay also reside in the control room but can reside elsewhere (offsite orin the magnet room). A single, typically dual channel, recorder may beused instead of two recorders as shown. The system may include a dryer37 in fluid communication with and upstream of the outgoingpneumotachometer 134 to dry gas in the expiratory gas flow path. Inspireand expire data from the pneumotachometers 34, 134, typically via theassociated recorders 34A, 134A, can be used to provide an MRIrespiratory gating input 20G for the gateway interface circuit 50 of theMR Scanner used to obtain MR image signal in a manner that is gated tothe respiratory cycle. The pneumotachometers can be Lilly typepneumotachometers.

The system 30′ may also include a receiving chamber 110 in fluidcommunication with the outgoing flow 33 o path residing downstream ofthe pneumotachometer 134 (where used). The chamber 110 can be a “mixing”chamber that collects a desired volume of output gas from the patient.The term “mixing” means that more than one sequential breath is allowedto equilibrate before external sampling of the oxygen and carbon dioxidelevels. An alternative is to sample the exhaled gases at the valve 35.The system 30′ can include an analyzer 112 that connects 111 to thechamber 110 that analyzes the content of the mixing chamber 110. Theanalyzer can be a real-time oxygen/CO2 analyzer. The term “real-time”means that the analysis can be carried out within about 1 second orless, typically substantially concurrently with, a measurement orreading at the chamber 110 or valve 35. The analyzer 112 can providedata for VO2 assessment/determination. The analyzer 112 can reside inthe MR control room but may also reside remote of the control room oreven in the magnet room (with proper shielding).

In some embodiments, a time constant τ for PFx/O2 and room air can bedetermined or used to calibrate the signal intensity and/or to helpdefine the desired times for obtaining image data for “gas trapping”evaluation. The volume “V” and/or content of the “V inhale and the Vexhale can be sampled. Vroom air and V PFx can be established based oninterpolations of N2/PFx at different concentrations (O₂ sampled, CO₂sampled). For example, for an input of 21% O₂ and 79% PFx, the outputgas in the chamber 110 downstream of the patient or sampled at valve 35can be analyzed. In a sample, there can be O₂ and CO₂, N₂ and H₂O. TheH₂O can be captured in a dryer 37 (weighed over a number of breaths).With the sequential breaths of the PFx mixture, the output gas is 79%Pfx (due to the extremely low solubility in water), oxygen (˜14%), CO₂and water. With the water ‘trapped’ in the drying system 37, it ispossible to know the composition of both the input gas mixture(certificate of analysis) and the output gas mixture with the samplingsystems so that global exchange of oxygen can be determined. This datacan act as a defining factor in the regional analysis of the ¹⁹F lungimages.

FIG. 3 illustrates another embodiment of the delivery system 30 and/orfurther or alternative features that can be used with any of thedelivery systems described or illustrated herein.

The system 30 may include a single flexible bag to assist in the passivedelivery of the gas 30 g, such as a Douglas bag 55. The bag 55 caninclude a temperature sensor 55 t and the system 30 can include aplurality of oxygen sensors 40 of the same or different types to confirmthat the oxygen level is at a desired level prior to delivery to asubject/patient.

The system 30 may also optionally include a scale or other weighingdevice 133 that can communicate with the electronic monitor 42 to alerta user if the supply is below a certain amount, e.g., when less than 5liters remain, or when below a certain weight corresponding to a lowlevel of the gas mixture. The monitor 42 can be the same monitor as theoxygen monitor or may be a separate monitor.

The pressurized canister 30 c of premixed gas 30 g can be held in aportable insulated case 33 j. The case 33 j can include insulation thatcan help keep the canister above about 10° C./50° F. during transportand/or storage. The case 33 j can include a thermometer or othertemperatures sensor that communicates with an on-board heat/cool sourceso as to be temperature controlled. The case can hold a single canister30 c or a plurality of canisters. The canister 30 c can hold a singlepatient bolus supply or multiple-patient bolus amounts. Examples ofsuitable single patient bolus supplies include about 1-100 liters,typically about 10-25 liters. The electronic monitor 36 m (FIG. 2A)and/or 42, where used, can reside inside the case or outside the case.The temperature sensor 36 can be placed inside the case instead ofdirectly on a canister in the case or in addition to individual sensors36 on each canister 30 c. A single monitor 36 m can monitor thetemperature of all temperature sensors for the respective canisters inthe case. The case can optionally include a scale or other weighingdevice that can communicate with the electronic monitor to alert a userif the supply is below a certain amount, e.g., when less than about 10%of the “full” weight remains. Alternately a pressure sensor sampling at35 can also detect a empty delivery bag at 55. Each canister 30 c in thecase can be in communication with such a scale or a single “dispensing”position in the case can include the scale and the canister 30 c inactive use can be placed in this position for capacity/level sensing sothat the delivery of the gas mixture 30 g during a procedure is notdisrupted by an inadvertent “empty” gas source.

FIG. 4A illustrates that the interface/gateway 50 can also include apower supply 50P and two operational modes 352, 353 as shown in FIG. 4A.The gateway/interface 50 can include safety indicators for the blockingcircuit 50C as shown in FIG. 4A. The lung (also known as “chest”) coilcan be configured to be “proton-blocked” allowing the MR scanner bodycoil to be used to make a proton image of the subject in substantiallythe same position as the subject during the ¹⁹F image. Thus, the protonblocked chest coil allows the body coil to obtain supplementalproton-based data image (without the interference of the ¹⁹F coil) whichcan be combined in a signal processor to provide a more detaileddiagnostic evaluation of the target region of interest. The blockingcircuit can be of a passive crossed diode design, active pin diodedesign or combination design. The purpose of the blocking circuitry whenactivated is to provide a high impedance at the 1H frequency. Indicatorson the blocking circuit power supply include general power (110V)available, blocking voltage (100 V reverse bias or −100 V) availableduring 1H transmit and blocking voltage disabled (10 V forward bias or+10 V) during 19F transmit. The coil 28 and the interface/gateway 50 canbe used with all other embodiments of the invention.

FIG. 4A also illustrates that the coil 28 can be a relatively flexiblewrap-around vest- or jacket-like coil with conductors positioned on boththe front and back of the chest. The rectangular dimensions can be about30-40 cm by about 110-140 cm to give nominal coverage of about 38-40 cmdiameter which may be particularly suitable for most adult patients.

For a 3.0 T system, the ¹H resonance is nominally 123-128 MHz while the¹⁹F resonance is about 115 MHz. These frequencies are relatively close.Thus, as discussed above the coil 28 can be proton blocked to allow ¹Himaging while the subject S is in the scanner 20M. The interface/gateway50 can be configured to allow a user to manually select and/or thesystem 10 to electronically select either a ¹H imaging mode or a ¹⁹Fimaging mode.

During at least a portion of the imaging session, before, after orduring delivery of the gas mixture 30 g, the body coil 23 can collect ¹Hsignal while the lung coil 28 collects ¹⁹F signal, thus allowingsubstantially concurrent, generally simultaneous, ¹H imaging with ¹⁹Fimaging. It is also contemplated that two frequency array coil can beused to obtain the two different frequency image data signalsconcurrently.

The system 10 can be configured to transmit and receive excitationpulses at both the ¹H and ¹⁹F resonances during a single imaging sessionand acquire image data signals using the body coil 23 and the lung coil28. To evaluate “wash in”, “wash out” or other ventilation information,the ¹⁹F imaging can continue for a plurality of respiratory cyclesbefore, during and/or after the gas mixture 30 g delivery, while thepatient breathes room air. For a “wash out” cycle from saturation of thegas mixture in the lungs, the wash out cycle can be carried out for aslong as there is detectable ¹⁹F signal, which is believed to be betweenabout 2-10 respiratory cycles in duration. The air breathing intakeimaging with ¹⁹F in lung spaces/tissue may allow gas trapping evaluationin both a regional and temporal manner. Examples of such images areshown in FIG. 22.

The system 10 can be configured to generate cine images of the lungs andlung spaces/airways. The cine images can be gated to the respiratorycycle. Gated imaging techniques are known. See, e.g., U.S. PatentApplication Publication No. 2008/0132778, the contents of which arehereby incorporated by reference as if recited in full herein.

As shown in FIG. 4B, the system 10 can include an automated cyclingsystem that electronically controls the gas delivery system 30 using,for example, a valve 30 v, located proximate the patient to close theflow path 33 f and a valve 30 v ₂ residing between the air intake andthe mask or mouthpiece 30 d to open the air flow path 33 a to allow thepatient to breathe air during a portion of the imaging session.Typically, the patient will breathe normal room air for the first 1-5minutes with ¹H MRI Tx/Rx operation. The patient will then be changedover to the gas mixture 30 g for 1-10 minutes, then switched back toroom air, during which time ¹⁹F signal can be obtained. The system 10can then close the air flow path 33 a and open the gas flow path 33 f todeliver the PFx gas mixture 30 g. The dispensing member (e.g., mask,nasal input or mouthpiece) can also be associated with a (one-way and/or“Y”) valve 55 that directs the exhaled room air or gas mixture to adownstream container such as a bag which can be a Douglas bag 56 (FIG.2A, 2B).

As shown in FIG. 4B, the gateway/interface 50 can include a respirationcontroller 50R that electronically controls the opening and closing ofthe valves 30 v ₁, 30 v ₂ during the imaging session. However, thevalves may also or alternatively allow for manual operation. However,the air to gas mixture controller 50R can be a separate circuit in adifferent device and can, for example, be interfaced to the scanner 20or a dedicated workstation.

The use of medical grade inert PFx gas and oxygen gas mixtures asimaging agents during MRI can provide regional ventilation information.The PFx gas attains a relatively high thermal polarization exceptionallyquickly which coupled with the large ¹⁹F MR signal, allowing for imagingventilation with a quality similar to that of hyperpolarized ¹²⁹Xe MRI,but at lower cost and with reduced technical complexity. Additionalparameters such as ‘gas trapping’, ‘wash-in’ and ‘wash-out’ time/dosecurves and ventilation defect severity can be determined with thesemixtures. Oxygen extraction can be indirectly determined from imagesobtained proximal to inspiration and compared to images >2 seconds postinspiration.

The scanner 20 can be configured to employ suitable MRI pulse sequences,including, for example, a gradient echo sequence in both or either 2Dand 3D modes, such as a GRE (gradient recalled echo) sequence and theGRE VIBE (Volume Interpolated Breath hold Examination) sequence modifiedfor very fast imaging. Both of these pulse sequences allow physiologicgating and standard imaging modes which allow for washout measurementsof regional ventilation. The currently contemplated imagingmethodologies do not have extraneous background signal, thus allowingthe use of non-selective excitations and extremely short echo times (TE)on the order of about 500 microseconds (μs) at high pixel bandwidths(BW) of about 1500 Hz/pixel (appropriate for SF6) and a lower BW ofabout 200 Hz/pixel) with a TE of about 0.8-1.2 milliseconds (ms) for PFP(because of the longer T2 and T2* for this agent). A 3D image (5 mmin-plane resolution and 15 mm slices) can be sampled in a few seconds,which allows a full 3-D volumetric reconstruction. Voxel dimensions canbe any suitable volumes but are typically 5 mm in-plane and 10-20 mmslices. However, it is also contemplated that alternate or optimizedpulse sequences will be developed for use with the PFx gas mixtures inthe future.

The pulse sequence can be generated to use a suitable flip angle toobtain the signal data of the target gas. FIGS. 5A-5C illustrateexamples of signal plots (signal versus flip angle) for TR=10 ms andTE=1 ms (TR refers to the repetition time and TE refers to echo time).For lung parenchyma (FIG. 5A), the T1 is about 1200 ms, and T2* is about1.8 ms. As shown in FIG. 5B, for SF6, T1=2 ms and T2*=1 ms. As shown inFIG. 5C, for PFP, T1=20 ms, T2*=10 ms. T1 is the decay time constant(T1) corresponding to the gas polarization life and T2* is a transverserelaxation time.

FIG. 6 illustrates exemplary operations that can be used to carry outmethods contemplated by embodiments of the present invention. Aperfluorinated gas and oxygen gas mixture is administered/delivered to apatient (block 100). Optionally, the delivery is a free-breathingdelivery of the gas mixture during the image data acquisition (block105) (note that step 105 could breath-held, free breathing or pacedbreathing where pacing could be accomplished with a visual or aural(tone) for the subject to match their breathing pattern). MR image dataof the lungs and/or lung airways of the patient are obtained duringand/or after the delivering step (block 110). At least one of thefollowing is generated using the obtained MR image data: (a) Cine MRIimages of lung ventilation; (b) gated dynamic MRI images of lungventilation; and (c) color-coded static images showing regionalventilation information over at least a portion of at least onerespiratory cycle; (d) at least one ventilation function index (whichcan include at least one different index for each of the right and leftlung or other compartmentalized measures for more site-specificinformation rather than the global conventional FEV measures); (e) aregional percent defect assessment based on MRI PFx (intensity) imagedata (that can also be for each of the right and left lungs); and (f) anoverlay plot using pneumotachometer data and MRI lung 1H and 19F images(block 120). The system may also be configured to display or provideFEV1 measures using both oxygen and the PFx gas used for the MRI images.It is contemplated that pulmonologists may be able to interpret the newdata better if conventional FEV1 measures are provided as a “baseline”or reference information (at least while the new technology is initiallyclinically implemented to facilitate clinician acceptance andunderstanding of the new measures of ventilation defects).

In some embodiments, the generating step generates a 3-D cine of lungfunction/ventilation (typically including image data collected based onfree-breathing of the PFx and O2 gas mixture) (block 124). The cineimages may be gated to the respiratory cycle and obtained over aplurality of breathing cycles using signal averaging.

Optionally, the method can also include the step of monitoring theoxygen level of the gas mixture and/or the patient during the deliveryand/or obtaining step (block 107).

Optionally, but typically, air-breath ¹H MR images of the patient areobtained before or after the PFx images during a single imaging session(block 112). This can be performed to include “wash in” and “wash outperiods” which may provide gas trapping or other ventilation defectinformation. See, e.g., FIGS. 15-19, 22 and 23. Optionally, lungventilation information is displayed with a color-coded map ofventilation and/or perfusion with the abnormalities, defects, ordeficiencies indicated in at least one visually dominant manner such ascolor, intensity and/or opacity based on the obtained MRI data (block114).

Optionally, visualizations of the lungs and/or lung airways aredisplayed so that the visualizations include image data from bothair-breaths using ¹H image data and PFx gas breaths using ¹⁹F MR imagedata (block 122).

The static and/or dynamic ventilation images can be based on fusedimages of registered ¹H image data and ¹⁹F image data obtainedconcurrently during a single imaging session.

The systems can include pneuomtachometers in the gas flow path (inspireside and expire side) that ca be used to obtain airflow data used togate the MR image acquisition (block 125). The systems/methods can beconfigured to automatically take VO2 measurements using a sensor on acollection chamber in the expire gas flow path during the imagingsession while the patient is in the MR Scanner (block 126).

In some embodiments, baseline ventilation images can be electronicallycompared to ventilation images taken during or after treatment with atherapeutic agent to analyze effect on lung function. The electroniccomparison can be based on intensity differences of spatially correlatedimaging data or changes in gas trapping function of the lung and thelike.

Generally stated, in some embodiments, a patient is positioned in a boreof an MRI scanner magnet 20M and exposed to a magnetic field. As is wellknown to those of skill in the art, the MRI scanner 20 typicallyincludes a super-conducting magnet 20M, gradient coils (with associatedpower supplies), a body and/or surface coil (transmit/receive RF coil),and a RF amplifier for generating RF pulses set at predeterminedfrequencies. The RF pulse(s) is transmitted to the patient with adefined pulse sequence and flip angle(s) to excite the target nuclei.The body 23 and surface (lung) coil 28 are each tuned to a differentselected frequency range to transmit the excitation pulses and toreceive signal in response to the TX pulse sequence generated by the MRIunit.

The patient inhales a quantity of the PFx/O2 gas mixture into thepulmonary region (i.e., lungs and trachea). After inhalation, thepatient can hold his or her breath for a predetermined time such as 5-20seconds. This can be described as a “breath-hold” delivery. However, inother embodiments, the patient can freely inhale the PFx/O2 gas mixtureduring the image session and signal acquisition.

During or shortly after inhalation of a suitable amount of gas mixture,the MRI scanner delivers a desired pulse sequence typically with a largeflip angle, such as, for example, a flip angle of about 40 degrees forPFP and a TR of 5 ms. As used herein, the term “large flip angle” refersto a flip angle which is greater than about 30 degrees and up to 90degrees.

The patient can then freely breathe air from the room and additional ¹⁹Fsignal can be obtained during additional respiratory cycles. Thedissipation or trapping of the signal can be evaluated to assessregional or global measures of ventilation.

FIG. 15 illustrates a series of steps that can be carried out along atime line to obtain different MRI signal data using both 1H and 19F MRI.As shown, the MR Scanner can be loaded (e.g., activated or selected torun) with 1H and 19F protocols (coils, pulse sequences, gating, etc. . .. ) (block 200). A smart trace and region grow algorithm can be used tooutline a lung cavity or cavities using 1H MRI (block 210). The regiongrow algorithm can be used to define the airspace(s) using 19F MRI(block 220). An example time course is set out at the right side margin,from time t=0 which is set to match the delivery of PFx/O₂ gas to timeN, which is a few breath cycles after the cessation of the PFx gas/O₂mixture and the intake of air (which is shown at time t=2). During thetime sequence, MRI image data can be obtained. At time t=0 to t=2,during a “wash in” period of PFx gas to an equilibrium or saturationperiod (t=2), image data is obtained (including images and/or cineimages). The previously defined lung cavity outline and airspace regionscan be used. The image data can be used to show a ventilation defect, bysubtracting the lung airspace from the lung cavity (blocks 225, 227,229). The PFx gas/O₂ mixture can be shut off and the patient can intakeair (t=3). Image data can be obtained during the “wash out” period timest=3 to t=n. The trapped volume of gas can be defined based on the lungairspace images (blocks 231, 233).

FIG. 16 is a schematic illustration of region based image analysis usingboth 1H and 19F (registered) MRI image data. As shown, two image datasets are obtained, one 1H MRI data set 250 ₁ and one 19F MRI data set250 ₂. The two image sets are aligned using, for example, 3-D normalizedmutual information co-registration (block 255). This matrix can beelectronically stored for future use. Lung masks can be created usingthe 1H MRI data set 250 ₁, the masks can be created using Region Growingand LiveWire or other suitable algorithms (block 252). {Examples of suchalgorithms are described in numerous texts, for example, in “Handbook ofMedical Imaging: Processing and Analysis”, Isaac N Bankman, Ed.,Academic Press, 2000} The masks can be filtered (e.g., weighted rank)and optionally dilated (block 254). These masks can be applied to theregistered 19F images 255R (e.g., NMI co-registered 19F image data).Summary parameters can be extracted from the 19F MRI image data usingthe applied masks (block 260). Summary parameters can be extracted byvolume and/or slice, including, for example, pixel intensity, pixelcount, histogram, summary statistics, 2D shape factors and the like. Theterm “summary statistics” includes, for example, mean, variance, range,etc. and the term “2-D shape factors” includes, for example, centroids,pixel weighted centroids, etc.

FIGS. 17A and 17B are tables of summary parameter data that is generatedfor one volume and a plurality of slices. The ventilation defect score(or “index”) for FIG. 17A is 39 while that for FIG. 17B is 116. Theventilation defect score can be determined by calculating the centroidin each slice as well as the image pixel intensity weighted centroid ineach slice. By summing the difference (x and y positions) of theseparameters, a volume displacement score can be obtained. For instance,if the image is homogeneous in intensity the ventilation defect score(“VDS”) would be zero. Larger values of the VDS give a single globalindex of inhomogeneous image intensity.

FIG. 18 illustrates a regional analysis using data from a graph of ¹⁹FPFx signal “S” over time of the PFx gas. At a defined time (t=x), aventilation defect can be identified based on a defined range orthreshold value. This defect can be based on the value at the definedtime (or ranges of values), and/or may include the slope or area underthe curve of a respective line. As shown, a substantially flat line fromt=0 to t=x can indicate a major ventilation defect (shown as 100%) whilethe upper line with the larger value at time t=x indicates noventilation defect. The intermediate line indicates a decrease infunction, shown as a 50% ventilation defect. In practice, the time canincorporate a few hundred seconds of image acquisition of a temporalarray of data (e.g., FIG. 22) and the ventilation defects can rank basedon regions that show asymptotic local signal maxima (no ventilationdefect).

FIG. 19 illustrates an example of an overlay plot or output display thatcan be provided to a clinician at a local worksite or a remote station.The display includes a time line of airflow data of the patient 302using at least one pneumotachometer with an overlay of MRI images,including one or more of images 305, 310, 320, 325, 330, taken at acorresponding time during the recording (with both air and PFx gasintake). The images can be thumbnail images that are shown over theairflow data or may be provided in an adjacent panel or windows. A UIassociated with a display that shows the overlay plot 300 can beconfigured to allow a user to select one image to enlarge it on theoverlay or in a separate window for ease of viewing.

Air flow rate is determined directly from the calibratedpneumotachometer 34 and volume is determined by integrating air flowwith respect to time. In practice, as the data is digitized thetrapezoidal rule applies.

For example, as shown inspire and expire breath hold normal air 1Himages, can be shown proximate to the time during the breath holdreflected by the airflow timeline. The inspire image can be before orafter the expire image. The MRI frequency can be adjusted and may bemarked on the overlay 300 as shown by text reference 315 (but arrows,different colors, or other indicia may also or alternatively be used).Inspire and Expire breath hold 19F MRI images may be obtained 320, 325over sequential or non-sequential breatholds (FIG. 22, shows 8sequential breathholds) and shown on the overlay plot 300. A cine run ofMR images 330 during free breathing of the PFx gas/O₂ mixture can beobtained and also shown or be accessible via a thumbnail and/or viewingpanel or window on the display shown as on the overlay plot 300.

FIGS. 20A and 20B illustrate a respective graph of pixel count versusPFx pixel intensity for each of a right and left lung of two differentpatients. While the PEV1 of each patient is almost exactly the same, theone of the left is an FEV1 of 0.62 for a 68 year old while the one onthe right is 0.61 for a 54 year old, the histogram ventilation defectanalysis shows a large defect difference.

Certain embodiments are directed to generating a ventilation defectalpha numeric or numeric index that can be used to facilitate clinicianand patient understanding or use of the PFx image data. The index can beright and left lung specific, e.g., an index for each lung of a patientsuch as R-10 (large right lung ventilation defect) and L-3 (lesserventilation defect in the left lung).

The index can be provided as a series of indices for each lung based ona standardized compartmentalized model of the lung. An example of acompartmentalized model 380 of the lungs is shown in FIG. 21. The modelcan be a quadrant or other multi-compartment 2-D or 3-D model based onthe PFx/O₂ gas MRI pixel signal. Each compartment of the model can beevaluated and/or populated using pixel intensity data and assigned anindex that is provided on a scale that represents a low or noventilation defect to a major or total ventilation defect. The scale cango from low to high or high to low. For example, the model can havebetween 1-20 compartments and a patient can have an associated number ofmeasures, e.g., for twelve compartments each compartment can have adefined associated identifier such as R1-R12 (right lung) and L1-L12(left lung), with each having an associated measure of ventilationdefect, e.g., from 0-10 or 0-100 and the like. This same data can beprovided in a visual “virtual” lung model or as a data set for aclinician to use. It is contemplated that a more regionalizedquantitative assessment of ventilation defects can help treat or trackdisease progression relative to the global FEV1 measure currently used.The index or indices can be provided along with conventional FEV1measures to facilitate clinician acceptance or use (and allow theclinician some historical evaluation information that may be helpfulwhen deciding on a therapeutic course of action).

The index can be provided as an integrated index (e.g., alphanumericalor numerical) which indicates the defect rating in each defined regionor as a global lung index (typically, at least one per lung). Theindexes can be provided as a ventilation defect index map showing aspatial distribution (pixel wise) of the lungs. The distribution can bebased on histogram data or other image signal data associated with 19Fat equilibrium and/or wash-in and/or wash-out.

Embodiments of the present invention may take the form of an entirelysoftware embodiment or (more likely) an embodiment combining softwareand hardware aspects, all generally referred to herein as a “circuit” or“module.” Furthermore, the present invention may take the form of acomputer program product on a computer-usable storage medium havingcomputer-usable program code embodied in the medium. Any suitablecomputer readable medium may be utilized including hard disks, CD-ROMs,optical storage devices, a transmission media such as those supportingthe Internet or an intranet, or magnetic storage devices. Some circuits,modules or routines may be written in assembly language or evenmicro-code to enhance performance and/or memory usage. It will befurther appreciated that the functionality of any or all of the programmodules may also be implemented using discrete hardware components, oneor more application specific integrated circuits (ASICs), or aprogrammed digital signal processor or microcontroller. Embodiments ofthe present invention are not limited to a particular programminglanguage.

Computer program code for carrying out operations of the presentinvention may be written in an object oriented programming language suchas Java®, Smalltalk or C++. However, the computer program code forcarrying out operations of the present invention may also be written inconventional procedural programming languages, such as the “C”programming language. The program code may execute entirely on theuser's computer, partly on the user's computer, as a stand-alonesoftware package, partly on the user's computer and partly on anothercomputer, local and/or remote or entirely on the other local or remotecomputer. In the latter scenario, the other local or remote computer maybe connected to the user's computer through a local area network (LAN)or a wide area network (WAN), or the connection may be made to anexternal computer (for example, through the Internet using an InternetService Provider).

The present invention is described herein, in part, with reference toflowchart illustrations and/or block diagrams of methods, apparatus(systems) and computer program products according to embodiments of theinvention. It will be understood that each block of the flowchartillustrations and/or block diagrams, and combinations of blocks in theflowchart illustrations and/or block diagrams, can be implemented bycomputer program instructions. These computer program instructions maybe provided to a processor of a general purpose computer, specialpurpose computer, or other programmable data processing apparatus toproduce a machine, such that the instructions, which execute via theprocessor of the computer or other programmable data processingapparatus, create means for implementing the functions/acts specified inthe flowchart and/or block diagram block or blocks.

These computer program instructions may also be stored in acomputer-readable memory that can direct a computer or otherprogrammable data processing apparatus to function in a particularmanner, such that the instructions stored in the computer-readablememory produce an article of manufacture including instruction meanswhich implement the function/act specified in the flowchart and/or blockdiagram block or blocks.

The computer program instructions may also be loaded onto a computer orother programmable data processing apparatus to cause a series ofoperational steps to be performed on the computer or other programmableapparatus to produce a computer implemented process such that theinstructions which execute on the computer or other programmableapparatus provide steps for implementing some or all of thefunctions/acts specified in the flowchart and/or block diagram block orblocks.

The flowcharts and block diagrams of certain of the figures hereinillustrate exemplary architecture, functionality, and operation ofpossible implementations of embodiments of the present invention. Inthis regard, each block in the flow charts or block diagrams representsa module, segment, or portion of code, which comprises one or moreexecutable instructions for implementing the specified logicalfunction(s). It should also be noted that in some alternativeimplementations, the functions noted in the blocks may occur out of theorder noted in the figures. For example, two blocks shown in successionmay in fact be executed substantially concurrently or the blocks maysometimes be executed in the reverse order or two or more blocks may becombined, depending upon the functionality involved.

FIG. 7 is a schematic illustration of a circuit or data processingsystem 190 that can be used with the system 10. The circuits and/or dataprocessing systems 190 data processing systems may be incorporated in adigital signal processor in any suitable device or devices. As shown inFIG. 7, the processor 410 communicates with an MRI scanner 20 and withmemory 414 via an address/data bus 448. The processor 410 can be anycommercially available or custom microprocessor. The MRI Scanner 20and/or processor 410 can communicate with an image analysis circuit 199and/or respiratory gating interface circuit 50C. The memory 414 isrepresentative of the overall hierarchy of memory devices containing thesoftware and data used to implement the functionality of the dataprocessing system. The memory 414 can include, but is not limited to,the following types of devices: cache, ROM, PROM, EPROM, EEPROM, flashmemory, SRAM, and DRAM.

FIG. 7 illustrates that the memory 414 may include several categories ofsoftware and data used in the data processing system: the operatingsystem 449; the application programs 454; the input/output (I/O) devicedrivers 458; and data 455. The data 455 can include patient-specificimage data. FIG. 7 also illustrates the application programs 454 caninclude a PFx Image Mode Data Collection Module 450, a 1H Image ModeData Collection Module 452, and a Cine and/or Regional VentilationInformation Image Data or Analysis Module 453.

As will be appreciated by those of skill in the art, the operatingsystems 449 may be any operating system suitable for use with a dataprocessing system, such as OS/2, AIX, DOS, OS/390 or System 390 fromInternational Business Machines Corporation, Armonk, N.Y., Windows CE,Windows NT, Windows95, Windows98, Windows2000, WindowsXP or otherWindows versions from Microsoft Corporation, Redmond, Wash., Unix orLinux or FreeBSO, Palm OS from Palm, Inc., Mac OS from Apple Computer,LabView, or proprietary operating systems. The I/O device drivers 458typically include software routines accessed through the operatingsystem 449 by the application programs 454 to communicate with devicessuch as I/O data port(s), data storage 455 and certain memory 414components. The application programs 454 are illustrative of theprograms that implement the various features of the data processingsystem and can include at least one application, which supportsoperations according to embodiments of the present invention. Finally,the data 455 represents the static and dynamic data used by theapplication programs 454, the operating system 449, the I/O devicedrivers 458, and other software programs that may reside in the memory414.

While the present invention is illustrated, for example, with referenceto the Modules 450, 452, 453 being application programs in FIG. 7, aswill be appreciated by those of skill in the art, other configurationsmay also be utilized while still benefiting from the teachings of thepresent invention. For example, the Modules 450, 452, 453 and/or mayalso be incorporated into the operating system 449, the I/O devicedrivers 458 or other such logical division of the data processingsystem. Thus, the present invention should not be construed as limitedto the configuration of FIG. 7 which is intended to encompass anyconfiguration capable of carrying out the operations described herein.Further, one or more of modules, i.e., Modules 450, 452, 453 cancommunicate with or be incorporated totally or partially in othercomponents, such as an MRI scanner 20, interface/gateway 50, imageanalysis circuit 199 and/or workstation 60.

The I/O data port can be used to transfer information between the dataprocessing system, the workstation, the MRI scanner, theinterface/gateway 50, the image analysis circuit 199 and/or anothercomputer system or a network (e.g., the Internet) or to other devices orcircuits controlled by the processor. These components may beconventional components such as those used in many conventional dataprocessing systems, which may be configured in accordance with thepresent invention to operate as described herein.

The ¹⁹F image data can be used to evaluate or assess pulmonaryphysiology and/or function. The image data can assess injury associatedwith and/or arising from disease states or conditions and other sourcessuch as, for example, drugs used to treat cancer or other conditions, aswell as chemical exposure (such as ingestion/inhalation of a poison orgas), environmental exposure, insect bites, snake venom, animal bites,viral, staff, or bacterial infections, as well as pulmonary status dueto other disease states, infectious or otherwise, aging, trauma, and thelike.

Embodiments of the invention can generate image data to assess,evaluate, diagnose, or monitor one or more of: a potential bioreactionto a transplant, such as lung transplant rejection, environmental lungdisorders, pneumonitis/fibrosis, pulmonary hypertension, pulmonaryinflammation such as interstitial and/or alveolar inflammation,interstitial lung diseases or disorders, pulmonary and/or alveolaredema, with or without alveolar hemorrhage, pulmonary emboli,drug-induced pulmonary disorders, diffuse lung disorders, chronicobstructive pulmonary disease, emphysema, asthma, pneumoconiosis,tuberculosis, pleural thickening, cystic fibrosis, pneumothorax,non-cardiogenic pulmonary edema, angioneurotic edema, angioedema, type Ialveolar epithelial cell necrosis, hyaline membrane formation, diffusealveolar damage such as proliferation of atypical type II pneumocytes,interstitial fibrosis, interstitial and/or alveolar infiltrates,alveolar septal edema, chronic pneumonitis/fibrosis, bronchospasm,bronchialitis obliterans, alveolar hemorrhage, aspiration pneumonia,hyercapnic respiratory failure, alveolitis/fibrosis syndrome, systemiclupus erythematosus, chronic eosinophilic pneumonia, acute respiratorydistress syndrome, and the like.

The lung can be a target of drug toxicity which can be evaluated byembodiments of the present invention. It is known for example, that manymedications, including chemotherapeutic drugs, anti-inflammatory drugs,anti-microbial agents, cardiac drugs and anticonvulsants can cause lunginjury including lung toxicity that can be progressive and result inrespiratory failure. See Diffuse Lung Disorders: A ComprehensiveClinical-Radiological Overview, Ch. 19, Drug-Induced PulmonaryDisorders, (Springer-Verlag London Ltd, 1999), the contents of which arehereby incorporated by reference as if recited in full herein. Examplesof drug-induced lung disorders that may be able to be evaluatedaccording to embodiments of the present invention include, but are notlimited to: pneumonitis/fibrosis, interstitial lung disease,interstitial or pulmonary honeycombing and/or fibrosis, hypersensitivitylung disease, non-cardiogenic pulmonary edema, systemic lupuserythematosus, bronchiolitis obliterans, pulmonary-renal syndrome,bronchospasm, alveolar hypoventilation, cancer chemotherapy-induced lungdisease, pulmonary nodules, acute chest pain syndrome, pulmonaryinfiltrates, pleural effusion and interstitial infiltrates, angioedema,cellular atypia, diffuse reticular or reticulonodular infiltrates,bilateral interstitial infiltrates, reduced diffusing capacity,parenchymal damage with alveolar epithelial hyperplasia and fibrosisand/or atypia, early onset pulmonary fibrosis, late-onset pulmonaryfibrosis, subacute interstitial lung disease.

Some of the above-conditions have been known to occur with specificdrugs, such as mitomycin and bleomycin, and, in certain embodiments ofthe invention, the PFX gas mixtures can be used to evaluate a patientthat is being treated with the potentially problematic drug to allowearlier intervention or alternate treatments should a lung exhibit adrug-induced disorder.

In some situations, patients can experience the onset of lung injury atthe early onset of treatment with a therapeutic agent or in a certainenvironment. However, presentation of the injury can be delayed. Incertain situations, the symptoms can present acutely with rapiddeterioration. In either case, earlier identification of the problem canallow earlier intervention.

Non-Limiting Examples will be discussed below.

EXAMPLE 1 Breath-Hold Imaging

FIGS. 8 and 9 illustrate 3D in-vivo human lung images of a healthy 60year old male obtained using MRI of a PFx/oxygen mixture. It is believedthat this imaging methodology has the potential to be a ‘game-changing’approach to evaluation and understanding of regional human lungventilation as well as in the efficacy evaluation of pharmaceuticalsinvolved in the treatment of lung disease. FIG. 8 is a panel of imagesobtained using a single breath hold of PFP. FIG. 8 shows 3D slicepartitions of the ¹⁹F PFx images (scan time 15 seconds). Note the signalin the gas mixture delivery tube in the top frames of FIG. 8. It iscontemplated that this signal data can be used as an externalcalibration standard for PFx signal.

FIG. 9 is a panel of three sets of images with the center set being a 3Dfusion of ¹H images (which are shown on the far left set of images as“base” images) co-registered with the PFx images (shown as the set onimages on the far right). The left panel are ¹H (base) images, the rightimages are PFx (match) images and the center images are 3D fusion imagesof ¹H and PFx (typically shown color-coded). The top row of imagescorresponds to transverse slices. The center row of images correspondsto coronal slices and the bottom row of images corresponds to sagittalslices. The images shown in FIGS. 8 and 9 are 3D breath-hold imagesusing PFP. The registered ¹H images shown in FIG. 9 were obtained withthe body coil concurrently with ¹⁹F signal obtained with the lung coilwhile the lung coil was actively proton blocked.

The PFP images were obtained using a 3D Gradient Refocused Echo (GRE)VIBE technique with a TR of 15 ms, a TE of 1.2 ms (non-selectiveexcitation), pixel bandwidth of 200 Hz, 64×64 pts, FOV=35 cm and coronalslice thickness of 15 mm in a single 15 second breath hold. Voxel volumewas 0.78 cm³ with a nominal SNR of 15:1. One feature of imaging suchagents is the lack of extraneous background signal allowing the use ofnon-selective excitation. Subjects were monitored for oxygen saturationcontinuously during the procedure with a fingertip pulse oximeter (InVivo MVS 3155).

Conventional 15 second breath hold studies typically exhibit a smalldrop in oxygen saturation by pulse oximetry (SaO2). A similar drop ofabout 1-2% was observed during breath-hold imaging while breathing thePFx/O2 mixtures. It is believed that with agents like PFP with longerT1's (and longer T2*), very fast imaging may benefit from flip angleoptimization (e.g., at a TR of about 5 ms, the optimum flip angle may beabout 40 degrees).

NEX (number of excitations) can be balanced against pixel bandwidth tooptimize SNR for different breathing patterns, free breathing and/orshort versus long breath-holds, FEV type manuvers, etc.

It is contemplated that, due to the optimum relaxation conditionsresulting from dominance of spin rotation relaxation on the PFx gasagents and the ability to get a signal from the incoming gas deliverysystem, embodiments of the present invention can allow a morequantitative analysis and display of lung ventilation.

EXAMPLE 2 MRI Cine Images of Lung Function

Cine images of breathing lungs can be generated as a “movie ofbreathing” that shows lung air spaces as they fill and evacuate during arespiratory cycle (including inhalation to exhalation) or during a FEV1maneuver to visualize or show where the gas goes or stays and/orventilation defects. The image data can be obtained over a plurality ofrespiratory cycles and the corresponding images (e.g., image slices) canbe co-registered illustrating anatomy changes and ventilation dataduring the respiratory cycle.

The cine images can be gated cine images. That is, the respiratorywaveform can be monitored and the image data registered (gated) to thepart of the cycle during which it was obtained. A typical respiratorycycle (inhale to exhale) is about 2-5 seconds long. Several images canbe taken, each in less than one second, and temporally registered ormatched to the associated part of the respiratory cycle. The image datacan be obtained over time and used to fill in the k-space (synchronizedto the respiratory cycle). The signal data can be averaged to improveSNR or track ventilation information over the respiratory cycle.

In this context, ‘gating’ is taken to mean any of a variety ofstrategies to detect and follow the respiratory cycle. One example wouldbe any of several types of respiratory bellows affixed about the chestand/or abdomen of the subject and further communicating with some formof pressure or motion transducer that allows the respiratory cycle to bemonitored by the MRI system so that image acquisition can besynchronized with the respiration of the subject. In another embodimentthe respiratory cycle may be monitored with optical or other means todetect chest wall or abdomen motion. In another embodiment so called‘navigator’ signals from the MRI data may be used to track therespiratory cycle. In all cases such signals would interface to the MRIsystem for synchronization of the MRI acquisition to the respiratorycycle of the subject. This synchronization can take the form ofacquiring a complete MRI acquisition in a portion of the respiratorycycle and/or segmenting the MRI acquisition over segments of therespiratory cycle and ‘recombining’ them during the reconstruction ofthe MRI images. One embodiment of this last approach is the basis for‘cine’ type imaging.

EXAMPLE 3 Free-Breathing Scans

¹⁹F gas (and ¹H) images of the human lung and airways can be obtained infree-breathing delivery to extract regional lung ventilationinformation. This imaging may be carried out so that the ventilationdefects are shown or identified in near real-time. Particular diseasestates may make one of the PFx agents preferable over another such aswhere breathing cycle time for respiratory/gated imaging may be diseasedependent.

The PFx gas agents will allow very rapid imaging with the possibility ofnear real time imaging of ventilation dynamics.

The image signal acquisition can be carried out to provide gated/cineimages with free breathing strategies. Other cycle-based imagegeneration techniques can also be used, such as, for example, spiral andpropeller with passive “free-breathing” delivery of the PFx/O2 gasmixtures and room air to provide dynamic visualizations or cines of lungmotion (which can include ventilation information/data for both inhaleand exhale portions of the breathing cycle).

EXAMPLE 4

Global and Regional Ventilation Evaluation by ¹⁹F and ¹H MRI

It is contemplated that a global and/or regional evaluation can becarried out in several manners including a spatial image analysis and/orin a histogram (local or global). The imaging session can be describedas having “early phase”, “equilibrium phase”, “room air” phase and,where used, an “FEV1” maneuver phase.

The “early phase” is associated to the first few breaths or during atemporally early part of a “breath-hold” signal acquisition during (forthe free breathing) or after (for the breath hold) delivery of thePFx/O2 gas mixture. The “equilibrium phase” is after the early phase.The FEV1 maneuver can be carried out while the patient is in a supineposition on the scanner bed. The signal acquisition can be during themaneuver or at the end of a forced expiratory maneuver. The “room air”phase is associated to the period after the patient intakes room airrather than the PFx gas mixture. The signal acquisition typically occursfor several breathing cycles until ¹⁹F signal is no longer detectable.

Global ventilation defects can be identified by the overall sum ofventilation defects for both lungs during one or more of each of thedifferent phases. In this embodiment, the total signal distribution inthe segmented lung can be evaluated by histogram or ‘tiles’ evaluationfor multimodal distribution. Regional ventilation can be evaluated usingsegmentation of the lung and by partition (reconstructed slice).Equilibrium image data and/or images can be compared to correspondingearly-phase and/or room-air image data and/or images for regionalventilation evaluation. A ventilation defect can be identified in thesignal data by a different pixel/voxel value relative to neighboringpixel/voxel values and/or changes in pixel/voxel intensity in subsequentimage ‘frames’.

Data from the room air phase can be used to evaluate gas-trapping in aregional as well as a temporal manner. Slope analysis or othermathematical interrogation can be used to identify the location andvolume of the gas-trapping regions.

FIGS. 10 and 11 illustrate images that can indicate ventilation defects(and/or gas trapping) as well as other information regarding regionallung function. The PFx gas image data can be presented so that it isshown in one color and the anatomical structure can be shown in another(or several others). FIG. 10 illustrates an example of a hydrogen (1H)image that provides a morphologic/morphmetric framework for functionalevaluation. FIG. 11 illustrates a series of color-coded PFx imagesduring a breathing cycle as the PFx gas is taken in and exhaled from thelungs. These segmented images allow the calculation of ventilationdefects and with temporal data, gas trapping. Again, because of therelaxation characteristics, it should be feasible to generatequantitative images of ventilation dynamics, ventilation defects and“gas trapping” in a matter of a few minutes of scanning with severalliters of the gases. It is noteworthy that the medical grades of thesegases in such mixtures with oxygen are currently in the price range ofbetween about 7-15 dollars per liter. Thus, even multi-liter quantitiesfor use as imaging contrast agents are not prohibitively expensive.

Airway spaces (e.g., alveolar spaces) can be imaged and biomarkersassociated with different disease states, conditions or physiologies canbe identified. Drug efficacy for treating different conditions may alsobe evaluated (for acute or chronic effect).

EXAMPLE 5 Gas Trapping and Histogram Analysis

From a ventilation information viewpoint, it should be easier to get ata more direct method of measuring gas trapping and should allow atemporal domain analysis of gas trapping not easily obtained withcurrent imaging strategies.

Gas trapping should be readily and quantitatively evaluated by cyclingbetween the inert PFx/O2 gas/oxygen mixture and room air (see, e.g., thediscussion with respect to FIG. 4B above).

It is contemplated that, because one can cycle between theadministration of PFx gas and room air, the loss of PFx signal over timecan be monitored as a measure of “gas trapping.” Unlike someperfluorinated compounds that have sensitivity to dissolved oxygen andhave been used as an oxygen probe, both SF6 and PFP have a dominant spinrotation relaxation mechanism and are essentially insensitive to theparamagnetic effect of molecular oxygen (triplet ground state). Thisallows spin density imaging that is proportional to the amount of PFx.This action can be used for ventilation evaluation as discussed aboveand for the evaluation of gas trapping. This approach should allowevaluation of both the volume of gas trapping as well as the time courseof the gas trapping. This latter temporal measure may provide a newdimension for the evaluation of gas trapping that is not currentlyavailable, even with high resolution CT (HRCT).

FIGS. 12A and 12B illustrate a “leaking glove” phantom which representsan example of temporal evaluation. In this example, a latex glove wasinflated in an acrylic sphere with a small hole in the glove, allowingthe glove to leak PFx into the sphere. FIGS. 12A and 12B (two exemplarytime-separated images) shows contrast between two concentrations of PFxin the sphere. Note the increase in the signal intensity as the gasleaks from the glove into the acrylic sphere (this is analogous to whatwould be seen with gas trapping after changing to room air).

FIGS. 13A and 13B illustrate two ROIs based on intensity from one frameof the ‘leaking glove’ phantom. The first ROI (Region 1, brighter ROI)is primarily on the interior of the object with a lighter shade thanRegion 2. The second ROI (Region 2) is primarily on the perimetersurrounding the Region 1 ROI and has a darker shade. The data can beanalyzed spatially as shown in FIGS. 13A and 13B, such as with regiongrowing. FIG. 13A shows two regions of interest ‘grown’ using a seededapproach while 13B shows a region of the entire ‘object’.

Alternatively, as shown in FIG. 14, the intensities of the object can besampled (occurrences versus intensity). FIG. 14 is a vigintile plot ofthe intensities extracted from the whole object, clearly demonstratingtwo intensity distributions. Table 1 below illustrates the mean and SDintensity and volume of the two ROIs in the left image and for the wholeobject.

TABLE 1 Signal and Volume Data of Glove in Sphere Phantom Signal SignalVolume Region Mean SD (cc) Region A ROI on left image (FIG. 12A) 353 38159 Region B ROI on left image (FIG. 12A) 184 61 185 Whole Object rightimage (FIG. 12B) 262 98 344

The image data can be obtained over a plurality of breathing orrespiratory cycles and the corresponding images (e.g., image slices) canbe co-registered.

Ventilation defects may also be identified by evaluating co-registeredimages of pixels/voxels using a linear function. If the slope of theintensity of co-registered pixels/voxels in a ROI is substantially zero,then there is no change in intensity and a gas trap may be identified.Alternatively, if the slope is negative, then the region likely does nothave a gas trap.

EXAMPLE 6 Spirometer Values Correlated with Regional Image VentilationData

Spirometric data can be collected in the supine position as MRI iscarried out while the patient is in this position, as supine positionwill change resting functional residual capacity volume and likelyinfluence FEV1/FVC. The spirometer measurements can be made in the MRIsuite just before the MRI session using an MRI compatible portablespirometry system. The density of MRI gas mixtures will differ from theair density in the room. Spirometry can be carried out on a patient withboth room air and the gas mixture (at least until an effect adjustmentfactor can be determined).

EXAMPLE 7 Clinical Trials

The question of regional ventilation in disorders such as COPD and otherlung pathologies or status, such as cystic fibrosis and lungtransplants, is becoming increasingly important. A recent editorial inthe New England Journal of Medicine addressed the issue of using changesin FEV1 (Forced Expiratory Volume in 1 second) as an endpoint intreatment trials (Reilly 2008). The comments were related to the UPLIFT(Understanding Potential Long-Term Impacts on Function with Tiotropium)trial (tiotropium vs. placebo) [NCT00144339] (Tashkin, Celli et al.2008). In this study, reported in the same issue, patients usingstandard respiratory medications (except inhaled anticholinergic drugs)were randomized to their existing treatment with either tiotropium orplacebo and followed for a 4-year period. While the treatment groupusing tiotropium had improvements in lung function, QOL (quality oflife) and fewer exacerbations in the 4-year study; there was nosignificant change in the rate of decline in FEV1 either before of afterbronchodilation. In a separate study called TORCH (Towards a Revolutionin COPD Health), trial patients were randomized to a combinationtreatment (fluticasone and salmeterol), each of the agents alone orplacebo [NCT00268216] (Calverley, Anderson et al. 2007). TORCH patientswere followed for a 3-year period where the primary outcome was deathfrom any cause. The reduction in mortality did not reach statisticalvalidity although there were benefits in secondary outcomes (e.g.frequency of exacerbations, spirometric values). The difference in FEV1for the dual agent arm versus placebo was 0.092 liters (95% CI0.075-0.108, p<0.001), although the mean baseline FEV1 for the treatedand placebo group was 1.24 and 1.26 liters respectively, yielding a 7%difference in the FEV1, a difference not generally considered clinicallyrelevant. The dominant question in the editorial and one facing studiesof COPD is the heterogeneity of the disorder and the current lack of agood diagnostic tool for stratification/screening of potential subjectsfor a treatment study.

The image data provided by embodiments of the invention can beparticularly suitable for diagnosing lung diseases or conditions inpatients, monitoring animals in drug discovery programs, monitoringpatients in and screening participants for clinical trials and assessingtherapeutic efficacy of therapeutic treatments on lungphysiology/conditions and diseases.

EXAMPLE 8 Assessing Regional Failure

In lung transplantation, evidence of regional failure is typicallyfollowed with bronchoscopy under sedation to evaluate pending failure ofthe transplant. In cystic fibrosis, a similar tactic exists forevaluation of the child's lungs using bronchoscopy under sedation.Embodiments of the invention can provide an alternative relativelysimple, non-invasive measure of ventilation using MRI image data.

EXAMPLE 9 Histograms

Ventilation defects can be identified using at least one histogram ofmean intensity voxels from MRI data of the perfluorinated gas. Thehistogram can represent a percentage versus mean intensity of voxelswithin a region of interest or identify clusters of voxels/pixels ofsimilar intensity and/or those that have a statistically significantvariance from “normal” intensity voxels/pixels.

The characteristic of the pixels/voxels that is evaluated via one ormore histograms may include intensity, color, saturation and/or othercharacteristics of individual pixels/voxels as well as relativecharacteristics of multiple pixels/voxels, such as contrast ratios orthe like. The evaluation can be carried out electronically and theresults of the evaluation can be provided to a user or may be providedfor further analysis. For example, a comparison of a first (baseline)image and a second image may be performed and a difference in averageintensity may be provided as results to a user. Furthermore, a histogramof the characteristic and/or differences in the characteristic betweenthe baseline and comparison images may be determined and provided as aresult. Additionally, the histogram could be pattern matched to alibrary of histogram profiles that are characteristic of particularinjuries, diseases and/or conditions. The results of the determinationmay, for example, be provided as part of a graphic user interface.

EXAMPLE 10 Identifying Biomarkers for Disease States

The image data provided by embodiments of the invention can beparticularly suitable for identifying genotypes of a lung disease, suchas COPD, or assessing whether the patient has large and/or small airwaydisease.

EXAMPLE 11 Lung Ventilation Defect Indexes

Lung specific or further detailed regional measures of ventilationdefects (and severity) can be generated using a lung ventilation index,e.g., R-5, L10. A standardized compartmental model of the lungs can beused to define multiple indexes in defined locations of each lungrepresenting degrees or measures of ventilation defects.

EXAMPLE 12 Display with Multiple MRI Lung Images and Flow Data Output

A workstation can have a display that can concurrently show multiple MRIlung images including “breath hold” inspire and expire images of roomair and/or PFx gas, cine free breathing PFx gas F19 images and wash-inand/or wash-out PFx F19 images. The display can show the images in atimeline corresponding to a graph or output of pneumotachomoeter data.

EXAMPLE 13 Ventilation Defect Severity Analysis Using Wash-in and/orWash-Out Parameters

FIG. 22 shows an array of images obtained during sequential breath holdswhile breathing the PFx mixtures to ‘equilibrium’. Frames 1-5 arewash-in and frames 6-8 are wash-out after switching to room air. Notethat the kinetics of wash-in and wash-out do not have to be equivalent.FIG. 23 shows an example of a ‘wash-in’/out plot from a region ofinterest analysis of FIG. 22 that can indicate an intake defect (duringwash in and/or at equilibrium) and/or gas trapping (during wash out) andthe like.

The present invention finds use for both veterinary and medicalapplications as well as animal studies for drug discovery and the like.The present invention may be advantageously employed for diagnosticevaluation and/or treatment of subjects, in particular human subjects,because it may be safer (e.g., less toxic) than other methods known inthe art (e.g., radioactive methods). In general, the inventive methodsmay be more readily accepted because they can avoid radioactivity ortoxic levels of chemicals or other agents. Subjects according to thepresent invention can be any animal subject, and are preferablymammalian subjects (e.g., humans, canines, felines, bovines, caprines,ovines, equines, rodents, porcines, and/or lagomorphs), and morepreferably are human subjects.

It is contemplated that embodiments of the present invention can be usedto identify ventilation defect volume and location(s), ventilationdefect severity, wash-in, wash-out, and/or ventilation dynamics whichmay be correlated to 1H data.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. Although a few exemplary embodiments ofthis invention have been described, those skilled in the art willreadily appreciate that many modifications are possible in the exemplaryembodiments without materially departing from the novel teachings andadvantages of this invention. Accordingly, all such modifications areintended to be included within the scope of this invention as defined inthe claims. In the claims, means-plus-function clauses are intended tocover the structures described herein as performing the recited functionand not only structural equivalents but also equivalent structures.Therefore, it is to be understood that the foregoing is illustrative ofthe present invention and is not to be construed as limited to thespecific embodiments disclosed, and that modifications to the disclosedembodiments, as well as other embodiments, are intended to be includedwithin the scope of the appended claims. The invention is defined by thefollowing claims, with equivalents of the claims to be included therein.

That which is claimed is:
 1. A method of generating lung ventilation information of a subject, comprising: providing a pressurized canister of a medical grade gas mixture of perfluorinated gas and oxygen holding the medical grade mixture in a gaseous phase; electronically obtaining a series of ¹⁹F magnetic resonance imaging (MRI) images of lungs of a subject associated with an inhaled amount of the perfluorinated gas and oxygen mixture from the pressurized canister during wash in and wash out of the perfluorinated gas and oxygen mixture; electronically obtaining ¹H MRI images of the lungs of the subject before or after or before and after obtaining the series of ¹⁹F MRI images while the subject breathes room air; electronically registering the obtained ¹⁹F MRI lung images to the obtained ¹H MRI lung images of the subject; electronically applying lung masks to the registered ¹⁹F images to define a perimeter of a lung cavity of a respective lung; and then electronically evaluating summary parameters of different volumes of the registered ¹⁹F lung images after applying the lung masks to generate lung ventilation information that identifies regional lung ventilation defects including gas trapping, wherein the obtaining, registering, applying and evaluating steps are carried out using at least one processor.
 2. The method of claim 1, wherein the electronically evaluating the summary parameters evaluates 2D shape factors of the different volumes.
 3. The method of claim 1, further comprising displaying a series of color-coded static lung images showing regional ventilation information over at least a portion of at least one respiratory cycle based at least in part on the evaluated summary parameters.
 4. The method of claim 1, further comprising displaying lung ventilation information on a color-coded lung map of ventilation and/or perfusion with at least one of abnormalities, defects and deficiencies shown with at least one of a defined color(s), intensity or opacity based on the summary parameters to thereby make the at least one of the abnormalities, defects and deficiencies visually dominant.
 5. The method of claim 1, further comprising electronically displaying a graph of ¹⁹F pixel intensity versus pixel count for each lung based on the pixels in the different volumes and different slices.
 6. The method of claim 1, further comprising generating histograms of mean intensity of voxels within regions of interest to identify clusters of voxels or those that have a statistically significant variance from normal intensity voxels.
 7. The method of claim 1, wherein the electronically evaluating comprises electronically generating data tables of pixel parameters for the different volumes with the tables comprising pixel centroids for respective slices in the different volumes.
 8. The method of claim 1, further comprising electronically providing a visual output of a graphic analysis fit to a lung model of ventilation wash-in and wash-out using the obtained ¹H and ¹⁹F MRI images and depicting functional information based on the summary parameters.
 9. The method of claim 1, further comprising displaying a lung map as a rendered visualization of one or more selected summary parameters that shows at least one of ventilation and perfusion information in a manner that illustrates relative degrees or measures of function in at least one of different colors, opacities and intensities.
 10. The method of claim 1, further comprising displaying three dimensional fusions of the obtained ¹H and ¹⁹F MRI images, color-coded to show ventilation defects based on the summary parameters.
 11. The method of claim 1, wherein the medical grade gas mixture is supplied at a pressure in the pressurized canister that is sufficiently low so that a dense gas component remains in a gaseous state under normal operating conditions of at least one of about 21 degrees C. or room temperature.
 12. The method of claim 1, wherein the electronically evaluating the summary parameters evaluates a plurality of the following: pixel intensity, pixel count, histograms, summary statistics and 2-D shape factors.
 13. The method of claim 1, wherein the electronically evaluating the summary parameters evaluates histograms of pixel intensity versus pixel count to identify ventilation defects.
 14. The method of claim 1, further comprising quantitatively analyzing lung function and/or electronically assessing regional ventilation of the lungs and providing a visualization of a map of the lungs illustrating regional ventilation defects of the lungs.
 15. The method of claim 1, further comprising quantitatively evaluating gas trapping by cycling between administration of the medical grade oxygen and gas mixture and administration of room air to the subject, wherein loss of ¹⁹F MRI signal over time associated with the different volumes and different slices during the cycling corresponds to a measure of gas trapping.
 16. A method of obtaining lung information of a subject, comprising: positioning a subject in a magnetic field associated with a high-field magnet of an MRI scanner; cyclically delivering, in vivo, via inhalation, a medical grade gas mixture and room air to the subject while the subject is in the magnetic field of the MRI scanner, wherein the medical grade gas mixture comprises between 20-79% inert perfluorinated gas and at least 20.5% oxygen gas obtained from a pressurized canister of the medical grade gas mixture, wherein the medical grade gas mixture is supplied at low pressure in the pressurized canister so that a dense gas component remains in a gaseous state under normal operating conditions of about 21 degrees C. and/or room temperature; electronically acquiring a series of ¹⁹F MRI lung space images associated with the inhalation of the cyclically delivered medical grade gas mixture and a series of ¹H MRI lung images, wherein the series of ¹⁹F MRI lung space images includes images acquired while the subject breathes room air to obtain wash-out and/or gas trapping data associated with a deplenishing amount of the ¹⁹F MRI signal as the subject breathes room air, and wherein the series of ¹H MRI lung images are acquired using the room air delivered to the subject before or after acquiring the series of ¹⁹F MRI lung space images or before and after acquiring the series of ¹⁹F MRI lung space images; registering the acquired ¹⁹F MRI lung images to the acquired ¹H MRI lung images of the subject; applying lung masks to the registered ¹⁹FMRI images to define a perimeter of a lung cavity of a respective lung; and then evaluating summary parameters by slice of a plurality of different volumes of the registered ¹⁹FMRI lung images after applying the lung masks to generate lung ventilation information that identifies regional lung ventilation defects including gas trapping, wherein the acquiring, registering, applying and evaluating are carried out using at least one processor.
 17. The method of claim 16, wherein the cyclical delivering is carried out so that a component ratio of the medical grade gas mixture that is drawn out of the pressurized canister remains constant, the method further comprising providing the pressurized canister with the medical grade gas mixture at the low pressure for the cyclical delivering with the medical grade gas mixture formulated to have a dew point of 0 degrees C. so that the medical grade gas mixture will not condense above this temperature.
 18. The method of claim 16, wherein the evaluating the summary parameters evaluates a plurality of the following: pixel intensity, pixel count, histograms, summary statistics and 2-D shape factors.
 19. The method of claim 18, further comprising electronically generating and displaying a visual output of a graphic analysis using the acquired ¹⁹F MRI images fit to a lung model of ventilation wash-in and wash-out depicting functional information of one or both lungs of the subject.
 20. The method of claim 18, further comprising generating histograms of mean intensity of voxels within regions of interest to identify clusters of voxels that have a statistically significant variance from normal intensity voxels.
 21. The method of claim 20, further comprising electronically evaluating the histograms to identify whether the subject is likely to have a ventilation and/or lung defect.
 22. An MRI system, comprising: an MRI scanner comprising a magnet with a magnetic field and at least one RF coil, the at least one RF coil being sized and configured to reside about lungs of a human patient; and a gas delivery system comprising: a pressurized canister of a medical grade gas mixture comprising perfluorinated gas in a level that is between 20-79% and oxygen gas in a level that is at least 20.5%, wherein the pressurized canister is at a sufficiently low pressure to hold the gas mixture in a gaseous state at room temperature; a gas flow path in communication with the pressurized canister of the medical grade gas mixture comprising at least one conduit extending from the canister to a free-breathing dispensing member adapted to reside over, on or in a respective patient while the patient resides inside the magnetic field to deliver the medical grade gas mixture; at least one oxygen sensor in communication with the gas flow path of the medical grade gas mixture; and at least one processor in communication with and/or onboard the MRI scanner, wherein the at least one processor: (i) obtains a series of ¹⁹F magnetic resonance imaging (MRI) images of lungs of the patient associated with the medical grade gas mixture during wash in and wash out of the perfluorinated gas and oxygen mixture; (ii) obtains ¹H MRI images of the lungs of the patient associated with room air inhaled by the patient before or after or before and after the series of ¹⁹F magnetic resonance imaging (MRI) images of lungs of the patient are obtained; (iii) registers the obtained ¹⁹F MRI lung images to ¹H MRI lung images of the patient; (iv) applies lung masks to the registered ¹⁹F images to define a perimeter of a lung cavity of a respective lung; and then (v) evaluates summary parameters from a plurality of slices of a plurality of different volumes of the registered ¹⁹F lung images after the lung masks are applied to generate lung ventilation information that identifies regional lung ventilation defects including gas trapping.
 23. The system of claim 22, wherein the evaluated summary parameters comprise 2D shape factors of the slices of the different volumes.
 24. The system of claim 22, wherein the at least one processor determines a time constant for the medical grade gas mixture to calibrate signal intensity based on a sample of an input of the delivered gas mixture and an exhaled sample of the delivered gas mixture to thereby define a global exchange of oxygen. 